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<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation [https://www.rcsb.org/structure/7PGR (7PGR)]. The identical chains that make up the dimer are colored lime and cyan. Two important domains in the function of Neurofibromin are highlighted with the GRD colored red and the Sec14-PH domain colored magenta.' scene='90/904315/Closed_spinning/3'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]<br /> Neurofibromin functions as a tumor suppressor protein by associating with [https://proteopedia.org/wiki/index.php/Ras Ras], a protein that signals for [https://en.wikipedia.org/wiki/Cell_proliferation cell proliferation] and growth. It has two conformations, the open, active conformation and the closed, inactive conformation (Figure 1). <ref name="Trovó-Marqui">PMID:16813595</ref> The change in conformation of Neurofibromin from open to closed regulates Ras activity, turning it off, thus stopping cell growth from continuing in excess. Neurofibromin is a [https://en.wikipedia.org/wiki/Dimer_(chemistry) dimer] made up of two identical [https://en.wikipedia.org/wiki/Monomer monomers] consisting of the Sec 14-PH domain and the GRD (Gap-related domain). The orientation of these domains is important for the interaction and binding of Ras to the Arginine finger in Neurofibromin, a key interaction in the regulation of Ras activity. Neurofibromin in its open conformation allows for the Ras association, unlike the closed conformation which is unable to associate with Ras and turn it off. <ref name="Naschberger">PMID:34707296</ref> The closed conformation is stabilized by a triad consisting of Cys1032, His1558, and His1576 and a Zinc atom. The molecular structure and detail of Neurofibromin have been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. Additionally, the structure of Neurofibromin isoform 2 revealed different functional states for Neurofibromin. <ref name="Naschberger">PMID:34707296</ref> Neurofibromin is encoded by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], which is located on chromosome 17. Mutations in the NF1 gene are associated with diseases including Neurofibromatosis Type 1, [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas], and cancers including glioblastoma, neuroblastoma, lung, ovarian, and breast cancer. <ref name="Lupton">PMID: 34887559 </ref> <ref name="Ratner">PMID:25877329</ref> <ref name="Abramowicz">PMID:25182393</ref><br /> <br /> == Function ==<br /> [[Image:mechanismofRas.png|500 px|left|thumb|Figure 2: Mechanism of Ras Regulation by Neurofibromin. One chain of the homodimer is represented in cyan with its important domains highlighted. Ras Guanine Nucleotide Exchange Factors (RasGEFs) are shown catalyzing the transition from an active to an inactive Ras molecule and Neurofibromin is shown catalyzing the reverse reaction]]<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division (Figure 2). Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase] that binds to [https://en.wikipedia.org/wiki/Guanosine_triphosphate GTP] and hydrolyzes it to [https://en.wikipedia.org/wiki/Guanosine_diphosphate GDP]. When Ras is active, it subsequently activates other proteins that stimulate cell growth and proliferation. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. Neurofibromin is brought to the membrane to associate with Ras by [https://en.wikipedia.org/wiki/SPRED1 SPRED1]. [https://medlineplus.gov/genetics/gene/spred1/ SPRED1] is a protein that helps regulate the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras/MAPK signaling pathway] responsible for the growth and proliferation of cells. Binding of SPRED1 to [https://en.wikipedia.org/wiki/RAF_kinase Raf] in the MAPK signaling pathway blocks the activation of Raf, halts the rest of the pathway, and stops cell growth and proliferation. Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations.<ref name="Naschberger">PMID:34707296</ref> The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg1276) present in the GRD domain of Neurofibromin. Arg1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. Ras binds to the arginine finger of Neurofibromin with its switch regions 1 and 2.<ref name="Trovó-Marqui">PMID:16813595</ref> When Arg1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division is inhibited. <ref name="Naschberger">PMID:34707296</ref> The positively charged arginine finger stabilizes the transition state for GTP hydrolysis by neutralizing the negative charges on GTP, which helps increase the speed of hydrolysis, fulfilling its catalytic function. <ref name="Trovó-Marqui">PMID:16813595</ref> <br /> <br /> <br /> == Structure ==<br /> [[Image:Neurofibromin_Cartoon_Domains.jpg|500 px|right|thumb|Figure 3: Neurofibromin Important Domains in one chain of the homodimer]]<br /> Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. The GRD and the Sec14-PH domain are centrally linked by an asymmetric, homodimeric core of four [https://en.wikipedia.org/wiki/Armadillo_repeat ARM] repeats and 27 [https://en.wikipedia.org/wiki/HEAT_repeat HEAT] repeats (Figure 3). The GRD and Sec14-PH domains extend out from the <scene name='90/904315/N-heat_arm/1'>N-HEAT/ARM</scene> core and then return to the <scene name='90/904315/C-heat_arm/1'>C-HEAT/ARM</scene> core. The orientation of the GRD and Sec-14 in relation to the N-HEAT/ARM and C-Heat/ARM determine what conformation neurofibromin is in. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the <scene name='90/904315/Open_conformation/4'>open conformation</scene>.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> == Conformational States ==<br /> <br /> === Closed Conformation ===<br /> In the <scene name='90/904315/Closed/3'>closed, inactive conformation</scene>, the GRD and Sec14-PH domains are rotated so Ras cannot bind. In this conformation, the GRD and Sec14-PH are inaccessible and inactive. Neurofibromin is held in the inactive state by a <scene name='90/904315/Closed_triade/7'>triad</scene> consisting of residues Cys1032, His1558, and His1576 that form a transition metal-binding site with zinc. The rigid organization of the <scene name='90/904315/Closed_triade/8'>triad in closed conformation</scene> keeps the GRD domain packed tightly on top of the Heat Arms in the Neurofibromin core. This tight compaction sterically occludes Neurofibromin from <scene name='90/904315/Closed_with_ras/2'>associating with Ras.</scene> In its active form, Ras and Neurofibromin will associate via an <scene name='90/904315/Arg_finger/5'>Arginine Finger</scene> (Arg1276). However, the <scene name='90/904315/Arg_finger/3'>steric hindrance</scene> from the Neurofibromin core in the closed conformation inhibits this association. Therefore, in the closed conformation, neurofibromin cannot catalyze GTP hydrolysis by Ras and Ras continues to signal for cell growth and proliferation.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> === Open Conformation ===<br /> In the <scene name='90/904315/Open_conformation/4'>open, active conformation</scene>, the GRD and Sec14-PH domain on one protomer have [https://youtu.be/I1I4uTVFR00 rotated] and become accessible for binding to Ras. This transition is initiated by the movement of the transition metal-binding site. The Cys1032, His1558, and His1576 Residues become separated and zinc is not able to bond. In the active form, one protomer has its GRD and Sec14-PH domains oriented oppositely from the inactive form (Figure 4). The GRD rotates -130° and the Sec14-PH domain rotates -90° away from the N-HEAT/ARM. Due to this rotation, Cys1032 is now located too far away, approximately 30 Å, from His1558 and His1576 which results in the loss of the metal-binding site and no formation of the <scene name='90/904315/Open_conformation_triade/6'>triad</scene>. The lack of the transition metal-binding site allows the GRD to orient itself to <scene name='90/904315/Openwithras/1'>associate with Ras</scene><ref name="Naschberger">PMID:34707296</ref>. This association positions the <scene name='90/904315/Open_conformation_arginine_fin/3'>Arginine Finger</scene> to help stabilize and orient a catalytic Ras residue (Q61) so that the gamma phosphate of GTP can be nucleophilically attacked <ref>PMID:33121128</ref>. When Neurofibromin is in the open, active conformation, <scene name='90/904315/Open_conformation_arginine_fin/4'>Arg1276</scene> is able to bind to Ras because there is no steric hindrance from the Neurofibromin core.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> [[Image:Domain Rotation.jpg|500 px|left|thumb|Figure 4: Rotation of the GRD and Sec14-PH domains from the closed conformation (7PGR) of neurofibromin to the open conformation (7PGT) of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently over 1485 mutations of <scene name='90/904315/Closed/3'>Neurofibromin</scene> have been identified that lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I.<ref name="Lupton">PMID: 34887559 </ref> <ref name="Abramowicz">PMID:25182393</ref> Mutations to the NF1 gene that prevents the interaction of Neurofibromin with Ras, remove this check on Ras-dependent cell proliferation and uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://en.wikipedia.org/wiki/Neurofibromatosis_type_I Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called [https://en.wikipedia.org/wiki/Caf%C3%A9_au_lait_spot cafe-au-lait macules], clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<ref name="Ratner">PMID:25877329</ref> <br /> <br /> Neurofibromin is also involved in the differentiation of [https://en.wikipedia.org/wiki/Neural_crest neural crest-derived cells], [https://en.wikipedia.org/wiki/Mesenchymal_stem_cell mesenchymal cells], [https://en.wikipedia.org/wiki/Neural_stem_cell neural cells], [https://en.wikipedia.org/wiki/Melanocyte melanocytes], and [https://en.wikipedia.org/wiki/Osteocyte bone cells]. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 point mutations identified to lead to a synthesis of truncated, non-functional protein. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases result from de novo mutations. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations in the NF1 gene have been found in sporadic cancers such as [https://en.wikipedia.org/wiki/Glioblastoma glioblastoma], [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma], [https://en.wikipedia.org/wiki/Lung_cancer lung cancer], [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian cancer], and [https://en.wikipedia.org/wiki/Breast_cancer breast cancer]. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3546849 Sandbox Reserved 1710 2022-04-18T19:16:23Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation [https://www.rcsb.org/structure/7PGR (7PGR)]. The identical chains that make up the dimer are colored lime and cyan. Two important domains in the function of Neurofibromin are highlighted with the GRD colored red and the Sec14-PH domain colored magenta.' scene='90/904315/Closed_spinning/3'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]<br /> Neurofibromin functions as a tumor suppressor protein by associating with [https://proteopedia.org/wiki/index.php/Ras Ras], a protein that signals [https://en.wikipedia.org/wiki/Cell_proliferation cell proliferation] and growth. <ref name="Trovó-Marqui">PMID:16813595</ref> The change in conformation of Neurofibromin from open to closed regulates Ras activity, turning it off, thus stopping cell growth from continuing in excess. Neurofibromin is a dimer made up of two identical monomers consisting of the Sec 14-PH domain and the GRD (Gap-related domain). The orientation of these domains is important for the interaction and binding of Ras to the Arginine finger in Neurofibromin, a key interaction in the regulation of Ras activity. Neurofibromin in its open conformation allows for the Ras association, unlike the closed conformation which is unable to associate with Ras and turn it off. <ref name="Naschberger">PMID:34707296</ref> The closed conformation is stabilized by a triad consisting of Cys 1032, His 1558, and His 1576 and a Zinc atom. The molecular structure and detail of Neurofibromin have been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. Additionally, the structure of Neurofibromin isoform 2 revealed different functional states for the Neurofibromin protein. <ref name="Naschberger">PMID:34707296</ref> Neurofibromin is encoded by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], which is located on chromosome 17. Mutations in the NF1 gene are associated with diseases including Neurofibromatosis Type 1, [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas], and cancers including glioblastoma, neuroblastoma, lung, ovarian, and breast cancer. <ref name="Lupton">PMID: 34887559 </ref> <ref name="Ratner">PMID:25877329</ref> <ref name="Abramowicz">PMID:25182393</ref><br /> <br /> <br /> == Function ==<br /> [[Image:Neurofibromin_Cartoon_Domains.jpg|500 px|left|thumb|Figure 2: Neurofibromin Important Domains in one chain of the homodimer]]<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase] that binds to GTP and hydrolyzes it to GDP. When Ras is active, it subsequently activates other proteins that stimulate cell growth and proliferation. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. Neurofibromin is brought to the membrane to associate with Ras by [https://en.wikipedia.org/wiki/SPRED1 SPRED1]. [https://medlineplus.gov/genetics/gene/spred1/ SPRED1] is a protein that helps regulate the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras/MAPK signaling pathway] responsible for the growth and proliferation of cells. Binding of SPRED1 to [https://en.wikipedia.org/wiki/RAF_kinase Raf] in the MAPK signaling pathway blocks the activation of Raf, halts the rest of the pathway, and stops cell growth and proliferation. Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations.<ref name="Naschberger">PMID:34707296</ref> The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg 1276) present in the GRD domain of Neurofibromin. Arg 1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. Ras binds to the arginine finger of Neurofibromin with its switch regions 1 and 2.<ref name="Trovó-Marqui">PMID:16813595</ref When Arg 1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division is inhibited. <ref name="Naschberger">PMID:34707296</ref> <br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. The GRD and the Sec14-PH domain are centrally linked by an asymmetric, homodimeric core of four [https://en.wikipedia.org/wiki/Armadillo_repeat ARM] repeats and 27 [https://en.wikipedia.org/wiki/HEAT_repeat HEAT] repeats. The GRD and Sec14-PH domains extend out from the <scene name='90/904315/N-heat_arm/1'>N-HEAT/ARM</scene> core and then return to the <scene name='90/904315/C-heat_arm/1'>C-HEAT/ARM</scene> core. The orientation of the GRD and Sec-14 in relation to the N-HEAT/ARM and C-Heat/ARM determine what conformation neurofibromin is in. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the <scene name='90/904315/Open_conformation/4'>open conformation</scene>.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> == Conformational States ==<br /> <br /> === Closed Conformation ===<br /> In the <scene name='90/904315/Closed/3'>closed, inactive conformation</scene>, the GRD and Sec14-PH domains are rotated so Ras cannot bind. In this conformation, the GRD and Sec14-PH are inaccessible and inactive. Neurofibromin is held in the inactive state by a <scene name='90/904315/Closed_triade/7'>triad</scene> consisting of residues Cys 1032, His 1558, and His 1576 that form a transition metal-binding site with zinc. The rigid organization of the <scene name='90/904315/Closed_triade/8'>triad in closed conformation</scene> keeps the GRD domain packed tightly on top of the Heat Arms in the Neurofibromin core. This tight compaction sterically occludes Neurofibromin from associating with Ras. In its active form, Ras and Neurofibromin will associate via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> (Arg 1276). However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, in the closed conformation, neurofibromin cannot catalyze GTP hydrolysis by Ras and Ras continues to signal for cell growth and proliferation.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> === Open Conformation ===<br /> In the <scene name='90/904315/Open_conformation/4'>open, active conformation</scene>, the GRD and Sec14-PH domain on one protomer have rotated and become accessible for binding to Ras. This transition is initiated by the movement of the transition metal-binding site. The Cys 1032, His 1558, and His 1576 Residues become separated and zinc is not able to bond. In the active form, one protomer has its GRD and Sec14-PH domains oriented oppositely from the inactive form. The GRD rotates -130° and the Sec14-PH domain rotates -90° away from the N-HEAT/ARM. Due to this rotation, Cys 1032 is now located too far away, approximately 30 Å, from His 1558 and His 1576 which results in the loss of the metal-binding site and no formation of the <scene name='90/904315/Open_conformation_triade/6'>triad</scene>. The lack of the transition metal-binding site allows the GRD to orient itself to associate with <scene name='90/904315/Ras_open_conformation/3'>Ras</scene> <ref name="Naschberger">PMID:34707296</ref>. This association positions the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> to help stabilize and orient a catalytic Ras residue (Q61) so that the gamma phosphate of GTP can be nucleophilically attacked <ref>PMID:33121128</ref>. When Neurofibromin is in the open, active conformation, Arg 1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> [[Image:Domain Rotation.jpg|500 px|left|thumb|Figure 3: Rotation of the GRD and Sec14-PH domains from the closed conformation (7PGR) of neurofibromin to the open conformation (7PGT) of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> <br /> <br /> == Disease and Medical Relevance ==<br /> Currently over 1485 mutations of Neurofibromin have been identified that lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I.<ref name="Lupton">PMID: 34887559 </ref> <ref name="Abramowicz">PMID:25182393</ref> Mutations to the NF1 gene that prevents the interaction of Neurofibromin with Ras, remove this check on Ras-dependent cell proliferation and uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://en.wikipedia.org/wiki/Neurofibromatosis_type_I Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called [https://en.wikipedia.org/wiki/Caf%C3%A9_au_lait_spot cafe-au-lait macules], clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<ref name="Ratner">PMID:25877329</ref> <br /> <br /> Neurofibromin is also involved in the differentiation of [https://en.wikipedia.org/wiki/Neural_crest neural crest-derived cells], [https://en.wikipedia.org/wiki/Mesenchymal_stem_cell mesenchymal cells], [https://en.wikipedia.org/wiki/Neural_stem_cell neural cells], [https://en.wikipedia.org/wiki/Melanocyte melanocytes], and [https://en.wikipedia.org/wiki/Osteocyte bone cells]. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 point mutations identified to lead to a synthesis of truncated, non-functional protein. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases result from de novo mutations. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations in the NF1 gene have been found in sporadic cancers such as [https://en.wikipedia.org/wiki/Glioblastoma glioblastoma], [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma], [https://en.wikipedia.org/wiki/Lung_cancer lung cancer], [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian cancer], and [https://en.wikipedia.org/wiki/Breast_cancer breast cancer]. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3546623 Sandbox Reserved 1710 2022-04-18T00:08:32Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation [https://www.rcsb.org/structure/7PGR (7PGR)]. The identical chains that make up the dimer are colored lime and cyan. Two important domains in the function of Neurofibromin are highlighted with the GRD colored red and the Sec14-PH domain colored magenta.' scene='90/904315/Closed_spinning/3'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]<br /> Neurofibromin functions as a tumor suppressor protein by associating with [https://proteopedia.org/wiki/index.php/Ras Ras], a protein that signals [https://en.wikipedia.org/wiki/Cell_proliferation cell proliferation] and growth. <ref name="Trovó-Marqui">PMID:16813595</ref> The change in conformation of Neurofibromin from open to closed regulates Ras activity, turning it off, thus stopping cell growth from continuing in excess. Neurofibromin is a dimer made up of two identical monomers consisting of the Sec 14-PH domain and the GRD (Gap-related domain). The orientation of these domains is important for the interaction and binding of Ras to the Arginine finger in Neurofibromin, a key interaction in the regulation of Ras activity. Neurofibromin in its open conformation allows for the Ras association, unlike the closed conformation which is unable to associate with Ras and turn it off. <ref name="Naschberger">PMID:34707296</ref> The closed conformation is stabilized by a triad consisting of Cys 1032, His 1558, and His 1576 and a Zinc atom. The molecular structure and detail of Neurofibromin have been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. Additionally, the structure of Neurofibromin isoform 2 revealed different functional states for the Neurofibromin protein. <ref name="Naschberger">PMID:34707296</ref> Neurofibromin is encoded by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], which is located on chromosome 17. Mutations in the NF1 gene are associated with diseases including Neurofibromatosis Type 1, [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas], and cancers including glioblastoma, neuroblastoma, lung, ovarian, and breast cancer. <ref name="Lupton">PMID: 34887559 </ref> <ref name="Ratner">PMID:25877329</ref> <ref name="Abramowicz">PMID:25182393</ref><br /> <br /> <br /> == Function ==<br /> [[Image:Neurofibromin_Cartoon_Domains.jpg|500 px|left|thumb|Figure 2: Neurofibromin Important Domains in one chain of the homodimer]]<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase] that binds to GTP and hydrolyzes it to GDP. When Ras is active, it subsequently activates other proteins that stimulate cell growth and proliferation. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. Neurofibromin is brought to the membrane to associate with Ras by [https://en.wikipedia.org/wiki/SPRED1 SPRED1]. [https://medlineplus.gov/genetics/gene/spred1/ SPRED1] is a protein that helps regulate the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras/MAPK signaling pathway] responsible for the growth and proliferation of cells. Binding of SPRED1 to [https://en.wikipedia.org/wiki/RAF_kinase Raf] in the MAPK signaling pathway blocks the activation of Raf, halts the rest of the pathway, and stops cell growth and proliferation. Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations.<ref name="Naschberger">PMID:34707296</ref> The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg 1276) present in the GRD domain of Neurofibromin. Arg 1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. When Arg 1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division is inhibited. <ref name="Naschberger">PMID:34707296</ref> (MECHANISTIC EXPLANATION).<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. The GRD and the Sec14-PH domain are centrally linked by an asymmetric, homodimeric core of four [https://en.wikipedia.org/wiki/Armadillo_repeat ARM] repeats and 27 [https://en.wikipedia.org/wiki/HEAT_repeat HEAT] repeats. The GRD and Sec14-PH domains extend out from the <scene name='90/904315/N-heat_arm/1'>N-HEAT/ARM</scene> core and then return to the <scene name='90/904315/C-heat_arm/1'>C-HEAT/ARM</scene> core. The orientation of the GRD and Sec-14 in relation to the N-HEAT/ARM and C-Heat/ARM determine what conformation neurofibromin is in. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the <scene name='90/904315/Open_conformation/4'>open conformation</scene>.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> == Conformational States ==<br /> <br /> === Closed Conformation ===<br /> In the <scene name='90/904315/Closed/3'>closed, inactive conformation</scene>, the GRD and Sec14-PH domains are rotated so Ras cannot bind. In this conformation, the GRD and Sec14-PH are inaccessible and inactive. Neurofibromin is held in the inactive state by a <scene name='90/904315/Closed_triade/7'>triad</scene> consisting of residues Cys 1032, His 1558, and His 1576 that form a transition metal-binding site with zinc. The rigid organization of the <scene name='90/904315/Closed_triade/8'>triad in closed conformation</scene> keeps the GRD domain packed tightly on top of the Heat Arms in the Neurofibromin core. This tight compaction sterically occludes Neurofibromin from associating with Ras. In its active form, Ras and Neurofibromin will associate via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> (Arg 1276). However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, in the closed conformation, neurofibromin cannot catalyze GTP hydrolysis by Ras and Ras continues to signal for cell growth and proliferation.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> === Open Conformation ===<br /> In the <scene name='90/904315/Open_conformation/4'>open, active conformation</scene>, the GRD and Sec14-PH domain on one protomer have rotated and become accessible for binding to Ras. This transition is initiated by the movement of the transition metal-binding site. The Cys 1032, His 1558, and His 1576 Residues become separated and zinc is not able to bond. In the active form, one protomer has its GRD and Sec14-PH domains oriented oppositely from the inactive form. The GRD rotates -130° and the Sec14-PH domain rotates -90° away from the N-HEAT/ARM. Due to this rotation, Cys 1032 is now located too far away, approximately 30 Å, from His 1558 and His 1576 which results in the loss of the metal-binding site and no formation of the <scene name='90/904315/Open_conformation_triade/6'>triad</scene>. The lack of the transition metal-binding site allows the GRD to orient itself to associate with <scene name='90/904315/Ras_open_conformation/3'>Ras</scene> <ref name="Naschberger">PMID:34707296</ref>. This association positions the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> to help stabilize and orient a catalytic Ras residue (Q61) so that the gamma phosphate of GTP can be nucleophilically attacked <ref>PMID:33121128</ref>. When Neurofibromin is in the open, active conformation, Arg 1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> [[Image:Domain Rotation.jpg|500 px|left|thumb|Figure 3: Rotation of the GRD and Sec14-PH domains from the closed conformation (7PGR) of neurofibromin to the open conformation (7PGT) of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> <br /> <br /> == Disease and Medical Relevance ==<br /> Currently over 1485 mutations of Neurofibromin have been identified that lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I.<ref name="Lupton">PMID: 34887559 </ref> <ref name="Abramowicz">PMID:25182393</ref> Mutations to the NF1 gene that prevents the interaction of Neurofibromin with Ras, remove this check on Ras-dependent cell proliferation and uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://en.wikipedia.org/wiki/Neurofibromatosis_type_I Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called [https://en.wikipedia.org/wiki/Caf%C3%A9_au_lait_spot cafe-au-lait macules], clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<ref name="Ratner">PMID:25877329</ref> <br /> <br /> Neurofibromin is also involved in the differentiation of [https://en.wikipedia.org/wiki/Neural_crest neural crest-derived cells], [https://en.wikipedia.org/wiki/Mesenchymal_stem_cell mesenchymal cells], [https://en.wikipedia.org/wiki/Neural_stem_cell neural cells], [https://en.wikipedia.org/wiki/Melanocyte melanocytes], and [https://en.wikipedia.org/wiki/Osteocyte bone cells]. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 point mutations identified to lead to a synthesis of truncated, non-functional protein. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases result from de novo mutations. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations in the NF1 gene have been found in sporadic cancers such as [https://en.wikipedia.org/wiki/Glioblastoma glioblastoma], [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma], [https://en.wikipedia.org/wiki/Lung_cancer lung cancer], [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian cancer], and [https://en.wikipedia.org/wiki/Breast_cancer breast cancer]. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3546621 Sandbox Reserved 1710 2022-04-18T00:02:53Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation [https://www.rcsb.org/structure/7PGR (7PGR)]. The identical chains that make up the dimer are colored lime and cyan. Two important domains in the function of Neurofibromin are highlighted with the GRD colored red and the Sec14-PH domain colored magenta.' scene='90/904315/Closed_spinning/3'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]<br /> Neurofibromin functions as a tumor suppressor protein by associating with [https://proteopedia.org/wiki/index.php/Ras Ras], a protein that signals [https://en.wikipedia.org/wiki/Cell_proliferation cell proliferation] and growth. <ref name="Trovó-Marqui">PMID:16813595</ref> The change in conformation of Neurofibromin from open to closed regulates Ras activity, turning it off, thus stopping cell growth from continuing in excess. Neurofibromin is a dimer made up of two identical monomers consisting of the Sec 14-PH domain and the GRD (Gap-related domain). The orientation of these domains is important for the interaction and binding of Ras to the Arginine finger in Neurofibromin, a key interaction in the regulation of Ras activity. Neurofibromin in its open conformation allows for the Ras association, unlike the closed conformation which is unable to associate with Ras and turn it off. <ref name="Naschberger">PMID:34707296</ref> The closed conformation is stabilized by a triad consisting of Cys 1032, His 1558, and His 1576 and a Zinc atom. The molecular structure and detail of Neurofibromin have been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. Additionally, the structure of Neurofibromin isoform 2 revealed different functional states for the Neurofibromin protein. <ref name="Naschberger">PMID:34707296</ref> Neurofibromin is encoded by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], which is located on chromosome 17. Mutations in the NF1 gene are associated with diseases including Neurofibromatosis Type 1, [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas], and cancers including glioblastoma, neuroblastoma, lung, ovarian, and breast cancer. <ref name="Lupton">PMID: 34887559 </ref> <ref name="Ratner">PMID:25877329</ref> <ref name="Abramowicz">PMID:25182393</ref><br /> <br /> <br /> == Function ==<br /> [[Image:Neurofibromin_Cartoon_Domains.jpg|500 px|left|thumb|Figure 2: Neurofibromin Important Domains in one chain of the homodimer]]<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase] that binds to GTP and hydrolyzes it to GDP. When Ras is active, it subsequently activates other proteins that stimulate cell growth and proliferation. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. Neurofibromin is brought to the membrane to associate with Ras by [https://en.wikipedia.org/wiki/SPRED1 SPRED1]. [https://medlineplus.gov/genetics/gene/spred1/ SPRED1] is a protein that helps regulate the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras/MAPK signaling pathway] responsible for the growth and proliferation of cells. Binding of SPRED1 to [https://en.wikipedia.org/wiki/RAF_kinase Raf] in the MAPK signaling pathway blocks the activation of Raf, halts the rest of the pathway, and stops cell growth and proliferation. Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations.<ref name="Naschberger">PMID:34707296</ref> The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg 1276) present in the GRD domain of Neurofibromin. Arg 1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. When Arg 1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division is inhibited. <ref name="Naschberger">PMID:34707296</ref> (MECHANISTIC EXPLANATION).<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. The GRD and the Sec14-PH domain are centrally linked by an asymmetric, homodimeric core of four [https://en.wikipedia.org/wiki/Armadillo_repeat ARM] repeats and 27 [https://en.wikipedia.org/wiki/HEAT_repeat HEAT] repeats. The GRD and Sec14-PH domains extend out from the <scene name='90/904315/N-heat_arm/1'>N-HEAT/ARM</scene> core and then return to the <scene name='90/904315/C-heat_arm/1'>C-HEAT/ARM</scene> core. The orientation of the GRD and Sec-14 in relation to the N-HEAT/ARM and C-Heat/ARM determine what conformation neurofibromin is in. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the <scene name='90/904315/Open_conformation/4'>open conformation</scene>.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> == Conformational States ==<br /> <br /> === Closed Conformation ===<br /> In the <scene name='90/904315/Closed/3'>closed, inactive conformation</scene>, the GRD and Sec14-PH domains are rotated so Ras cannot bind. In this conformation, the GRD and Sec14-PH are inaccessible and inactive. Neurofibromin is held in the inactive state by a <scene name='90/904315/Closed_triade/7'>triad</scene> consisting of residues Cys 1032, His 1558, and His 1576 that form a transition metal-binding site with zinc. The rigid organization of the <scene name='90/904315/Closed_triade/8'>triad in closed conformation</scene> keeps the GRD domain packed tightly on top of the Heat Arms in the Neurofibromin core. This tight compaction sterically occludes Neurofibromin from associating with Ras. In its active form, Ras and Neurofibromin will associate via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> (Arg 1276). However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, in the closed conformation, neurofibromin cannot catalyze GTP hydrolysis by Ras and Ras continues to signal for cell growth and proliferation.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> === Open Conformation ===<br /> In the <scene name='90/904315/Open_conformation/4'>open, active conformation</scene>, the GRD and Sec14-PH domain on one protomer have rotated and become accessible for binding to Ras. This transition is initiated by the movement of the transition metal-binding site. The Cys 1032, His 1558, and His 1576 Residues become separated and zinc is not able to bond. In the active form, one protomer has its GRD and Sec14-PH domains oriented oppositely from the inactive form. The GRD rotates -130° and the Sec14-PH domain rotates -90° away from the N-HEAT/ARM. Due to this rotation, Cys 1032 is now located too far away, approximately 30 Å, from His 1558 and His 1576 which results in the loss of the metal-binding site and no formation of the <scene name='90/904315/Open_conformation_triade/6'>triad</scene>. The lack of the transition metal-binding site allows the GRD to orient itself to associate with <scene name='90/904315/Ras_open_conformation/3'>Ras</scene>. This association positions the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> to help stabilize and orient a catalytic Ras residue (Q61) so that the gamma phosphate of GTP can be nucleophilically attacked <ref>PMID:33121128</ref>. When Neurofibromin is in the open, active conformation, Arg 1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> [[Image:Domain Rotation.jpg|500 px|left|thumb|Figure 3: Rotation of the GRD and Sec14-PH domains from the closed conformation (7PGR) of neurofibromin to the open conformation (7PGT) of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> <br /> <br /> == Disease and Medical Relevance ==<br /> Currently over 1485 mutations of Neurofibromin have been identified that lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I.<ref name="Lupton">PMID: 34887559 </ref> <ref name="Abramowicz">PMID:25182393</ref> Mutations to the NF1 gene that prevents the interaction of Neurofibromin with Ras, remove this check on Ras-dependent cell proliferation and uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://en.wikipedia.org/wiki/Neurofibromatosis_type_I Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called [https://en.wikipedia.org/wiki/Caf%C3%A9_au_lait_spot cafe-au-lait macules], clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<ref name="Ratner">PMID:25877329</ref> <br /> <br /> Neurofibromin is also involved in the differentiation of [https://en.wikipedia.org/wiki/Neural_crest neural crest-derived cells], [https://en.wikipedia.org/wiki/Mesenchymal_stem_cell mesenchymal cells], [https://en.wikipedia.org/wiki/Neural_stem_cell neural cells], [https://en.wikipedia.org/wiki/Melanocyte melanocytes], and [https://en.wikipedia.org/wiki/Osteocyte bone cells]. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 point mutations identified to lead to a synthesis of truncated, non-functional protein. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases result from de novo mutations. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations in the NF1 gene have been found in sporadic cancers such as [https://en.wikipedia.org/wiki/Glioblastoma glioblastoma], [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma], [https://en.wikipedia.org/wiki/Lung_cancer lung cancer], [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian cancer], and [https://en.wikipedia.org/wiki/Breast_cancer breast cancer]. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3546615 Sandbox Reserved 1710 2022-04-17T23:36:40Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation [https://www.rcsb.org/structure/7PGR (7PGR)]. The identical chains that make up the dimer are colored lime and cyan. Two important domains in the function of Neurofibromin are highlighted with the GRD colored red and the Sec14-PH domain colored magenta.' scene='90/904315/Closed_spinning/3'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]<br /> Neurofibromin functions as a tumor suppressor protein by associating with [https://proteopedia.org/wiki/index.php/Ras Ras], a protein that signals [https://en.wikipedia.org/wiki/Cell_proliferation cell proliferation] and growth. <ref name="Trovó-Marqui">PMID:16813595</ref> The change in conformation of Neurofibromin from open to closed regulates Ras activity, turning it off, thus stopping cell growth from continuing in excess. Neurofibromin is a dimer made up of two identical monomers consisting of the Sec 14-PH domain and the GRD (Gap-related domain). The orientation of these domains is important for the interaction and binding of Ras to the Arginine finger in Neurofibromin, a key interaction in the regulation of Ras activity. Neurofibromin in its open conformation allows for the Ras association, unlike the closed conformation which is unable to associate with Ras and turn it off. <ref name="Naschberger">PMID:34707296</ref> The closed conformation is stabilized by a triad consisting of Cys 1032, His 1558, and His 1576 and a Zinc atom. The molecular structure and detail of Neurofibromin have been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. Additionally, the structure of Neurofibromin isoform 2 revealed different functional states for the Neurofibromin protein. <ref name="Naschberger">PMID:34707296</ref> Neurofibromin is encoded by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], which is located on chromosome 17. Mutations in the NF1 gene are associated with diseases including Neurofibromatosis Type 1, [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas], and cancers including glioblastoma, neuroblastoma, lung, ovarian, and breast cancer. <ref name="Lupton">PMID: 34887559 </ref> <ref name="Ratner">PMID:25877329</ref> <ref name="Abramowicz">PMID:25182393</ref><br /> <br /> <br /> == Function ==<br /> [[Image:Neurofibromin_Cartoon_Domains.jpg|500 px|left|thumb|Figure 2: Neurofibromin Important Domains in one chain of the homodimer]]<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase] that binds to GTP and hydrolyzes it to GDP. When Ras is active, it subsequently activates other proteins that stimulate cell growth and proliferation. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. Neurofibromin is brought to the membrane to associate with Ras by [https://en.wikipedia.org/wiki/SPRED1 SPRED1]. [https://medlineplus.gov/genetics/gene/spred1/ SPRED1] is a protein that helps regulate the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras/MAPK signaling pathway] responsible for the growth and proliferation of cells. Binding of SPRED1 to [https://en.wikipedia.org/wiki/RAF_kinase Raf] in the MAPK signaling pathway blocks the activation of Raf, halts the rest of the pathway, and stops cell growth and proliferation. Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations. The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg 1276) present in the GRD domain of Neurofibromin. Arg 1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. When Arg 1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division is inhibited. (MECHANISTIC EXPLANATION).<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. The GRD and the Sec14-PH domain are centrally linked by an asymmetric, homodimeric core of four [https://en.wikipedia.org/wiki/Armadillo_repeat ARM] repeats and 27 [https://en.wikipedia.org/wiki/HEAT_repeat HEAT] repeats. The GRD and Sec14-PH domains extend out from the <scene name='90/904315/N-heat_arm/1'>N-HEAT/ARM</scene> core and then return to the <scene name='90/904315/C-heat_arm/1'>C-HEAT/ARM</scene> core. The orientation of the GRD and Sec-14 in relation to the N-HEAT/ARM and C-Heat/ARM determine what conformation neurofibromin is in. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the <scene name='90/904315/Open_conformation/4'>open conformation</scene>.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> == Conformational States ==<br /> <br /> === Closed Conformation ===<br /> In the <scene name='90/904315/Closed/3'>closed, inactive conformation</scene>, the GRD and Sec14-PH domains are rotated so Ras cannot bind. In this conformation, the GRD and Sec14-PH are inaccessible and inactive. Neurofibromin is held in the inactive state by a <scene name='90/904315/Closed_triade/7'>triad</scene> consisting of residues Cys 1032, His 1558, and His 1576 that form a transition metal-binding site with zinc. The rigid organization of the <scene name='90/904315/Closed_triade/8'>triad in closed conformation</scene> keeps the GRD domain packed tightly on top of the Heat Arms in the Neurofibromin core. This tight compaction sterically occludes Neurofibromin from associating with Ras. In its active form, Ras and Neurofibromin will associate via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> (Arg 1276). However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, in the closed conformation, neurofibromin cannot catalyze GTP hydrolysis by Ras and Ras continues to signal for cell growth and proliferation.<br /> <br /> === Open Conformation ===<br /> In the <scene name='90/904315/Open_conformation/4'>open, active conformation</scene>, the GRD and Sec14-PH domain on one protomer have rotated and become accessible for binding to Ras. This transition is initiated by the movement of the transition metal-binding site. The Cys 1032, His 1558, and His 1576 Residues become separated and zinc is not able to bond. In the active form, one protomer has its GRD and Sec14-PH domains oriented oppositely from the inactive form. The GRD rotates -130° and the Sec14-PH domain rotates -90° away from the N-HEAT/ARM. Due to this rotation, Cys 1032 is now located too far away, approximately 30 Å, from His 1558 and His 1576 which results in the loss of the metal-binding site and no formation of the <scene name='90/904315/Open_conformation_triade/6'>triad</scene>. The lack of the transition metal-binding site allows the GRD to orient itself to associate with <scene name='90/904315/Ras_open_conformation/3'>Ras</scene>. This association positions the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> to help stabilize and orient a catalytic Ras residue (Q61) so that the gamma phosphate of GTP can be nucleophilically attacked <ref>PMID:33121128</ref>. When Neurofibromin is in the open, active conformation, Arg 1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:Domain Rotation.jpg|500 px|left|thumb|Figure 3: Rotation of the GRD and Sec14-PH domains from the closed conformation (7PGR) of neurofibromin to the open conformation (7PGT) of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> <br /> <br /> == Disease and Medical Relevance ==<br /> Currently over 1485 mutations of Neurofibromin have been identified that lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I.<ref name="Lupton">PMID: 34887559 </ref> <ref name="Abramowicz">PMID:25182393</ref> Mutations to the NF1 gene that prevents the interaction of Neurofibromin with Ras, remove this check on Ras-dependent cell proliferation and uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://en.wikipedia.org/wiki/Neurofibromatosis_type_I Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called [https://en.wikipedia.org/wiki/Caf%C3%A9_au_lait_spot cafe-au-lait macules], clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<ref name="Ratner">PMID:25877329</ref> <br /> <br /> Neurofibromin is also involved in the differentiation of [https://en.wikipedia.org/wiki/Neural_crest neural crest-derived cells], [https://en.wikipedia.org/wiki/Mesenchymal_stem_cell mesenchymal cells], [https://en.wikipedia.org/wiki/Neural_stem_cell neural cells], [https://en.wikipedia.org/wiki/Melanocyte melanocytes], and [https://en.wikipedia.org/wiki/Osteocyte bone cells]. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 point mutations identified to lead to a synthesis of truncated, non-functional protein. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases result from de novo mutations. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations in the NF1 gene have been found in sporadic cancers such as [https://en.wikipedia.org/wiki/Glioblastoma glioblastoma], [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma], [https://en.wikipedia.org/wiki/Lung_cancer lung cancer], [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian cancer], and [https://en.wikipedia.org/wiki/Breast_cancer breast cancer]. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3546614 Sandbox Reserved 1710 2022-04-17T23:34:21Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation [https://www.rcsb.org/structure/7PGR (7PGR)]. The identical chains that make up the dimer are colored lime and cyan. Two important domains in the function of Neurofibromin are highlighted with the GRD colored red and the Sec14-PH domain colored magenta.' scene='90/904315/Closed_spinning/3'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]<br /> Neurofibromin functions as a tumor suppressor protein by associating with [https://proteopedia.org/wiki/index.php/Ras Ras], a protein that signals [https://en.wikipedia.org/wiki/Cell_proliferation cell proliferation] and growth. <ref name="Trovó-Marqui">PMID:16813595</ref> The change in conformation of Neurofibromin from open to closed regulates Ras activity, turning it off, thus stopping cell growth from continuing in excess. Neurofibromin is a dimer made up of two identical monomers consisting of the Sec 14-PH domain and the GRD (Gap-related domain). The orientation of these domains is important for the interaction and binding of Ras to the Arginine finger in Neurofibromin, a key interaction in the regulation of Ras activity. Neurofibromin in its open conformation allows for the Ras association, unlike the closed conformation which is unable to associate with Ras and turn it off. <ref name="Naschberger">PMID:34707296</ref> The closed conformation is stabilized by a triad consisting of Cys 1032, His 1558, and His 1576 and a Zinc atom. The molecular structure and detail of Neurofibromin have been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. Additionally, the structure of Neurofibromin isoform 2 revealed different functional states for the Neurofibromin protein. <ref name="Naschberger">PMID:34707296</ref> Neurofibromin is encoded by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], which is located on chromosome 17. Mutations in the NF1 gene are associated with diseases including Neurofibromatosis Type 1, [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas], and cancers including glioblastoma, neuroblastoma, lung, ovarian, and breast cancer. <ref name="Lupton">PMID: 34887559 </ref> <ref name="Ratner">PMID:25877329</ref> <ref name="Abramowicz">PMID:25182393</ref><br /> <br /> <br /> == Function ==<br /> [[Image:Neurofibromin_Cartoon_Domains.jpg|500 px|left|thumb|Figure 2: Neurofibromin Important Domains in one chain of the homodimer]]<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase] that binds to GTP and hydrolyzes it to GDP. When Ras is active, it subsequently activates other proteins that stimulate cell growth and proliferation. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. Neurofibromin is brought to the membrane to associate with Ras by [https://en.wikipedia.org/wiki/SPRED1 SPRED1]. [https://medlineplus.gov/genetics/gene/spred1/ SPRED1] is a protein that helps regulate the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras/MAPK signaling pathway] responsible for the growth and proliferation of cells. Binding of SPRED1 to [https://en.wikipedia.org/wiki/RAF_kinase Raf] in the MAPK signaling pathway blocks the activation of Raf, halts the rest of the pathway, and stops cell growth and proliferation. Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations. The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg 1276) present in the GRD domain of Neurofibromin. Arg 1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. When Arg 1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division is inhibited. (MECHANISTIC EXPLANATION).<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. The GRD and the Sec14-PH domain are centrally linked by an asymmetric, homodimeric core of four [https://en.wikipedia.org/wiki/Armadillo_repeat ARM] repeats and 27 [https://en.wikipedia.org/wiki/HEAT_repeat HEAT] repeats. The GRD and Sec14-PH domains extend out from the <scene name='90/904315/N-heat_arm/1'>N-HEAT/ARM</scene> core and then return to the <scene name='90/904315/C-heat_arm/1'>C-HEAT/ARM</scene> core. The orientation of the GRD and Sec-14 in relation to the N-HEAT/ARM and C-Heat/ARM determine what conformation neurofibromin is in. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the <scene name='90/904315/Open_conformation/4'>open conformation</scene>.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> == Conformational States ==<br /> <br /> === Closed Conformation ===<br /> In the <scene name='90/904315/Closed/3'>closed, inactive conformation</scene>, the GRD and Sec14-PH domains are rotated so Ras cannot bind. In this conformation, the GRD and Sec14-PH are inaccessible and inactive. Neurofibromin is held in the inactive state by a <scene name='90/904315/Closed_triade/7'>triad</scene> consisting of residues Cys 1032, His 1558, and His 1576 that form a transition metal-binding site with zinc. The rigid organization of the <scene name='90/904315/Closed_triade/8'>triad in closed conformation</scene> keeps the GRD domain packed tightly on top of the Heat Arms in the Neurofibromin core. This tight compaction sterically occludes Neurofibromin from associating with Ras. In its active form, Ras and Neurofibromin will associate via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> (Arg 1276). However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, in the closed conformation, neurofibromin cannot catalyze GTP hydrolysis by Ras and Ras continues to signal for cell growth and proliferation.<br /> <br /> === Open Conformation ===<br /> In the <scene name='90/904315/Open_conformation/4'>open, active conformation</scene>, the GRD and Sec14-PH domain on one protomer have rotated and become accessible for binding to Ras. This transition is initiated by the movement of the transition metal-binding site. The Cys 1032, His 1558, and His 1576 Residues become separated and zinc is not able to bond. In the active form, one protomer has its GRD and Sec14-PH domains oriented oppositely from the inactive form. The GRD rotates -130° and the Sec14-PH domain rotates -90° away from the N-HEAT/ARM. Due to this rotation, Cys 1032 is now located too far away, approximately 30 Å, from His 1558 and His 1576 which results in the loss of the metal-binding site and no formation of the <scene name='90/904315/Open_conformation_triade/6'>triad</scene>. The lack of the transition metal-binding site allows the GRD to orient itself to associate with <scene name='90/904315/Ras_open_conformation/3'>Ras</scene>. This association positions the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> to help stabilize and orient a catalytic Ras residue (Q61) so that the gamma phosphate of GTP can be nucleophilically attacked <ref>PMID:33121128</ref>. When Neurofibromin is in the open, active conformation, Arg 1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:Domain Rotation.jpg|500 px|left|thumb|Figure 3: Rotation of the GRD and Sec14-PH domains from the closed conformation (7PGR) of neurofibromin to the open conformation (7PGT) of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> <br /> <br /> == Disease and Medical Relevance ==<br /> Currently over 1485 mutations of Neurofibromin have been identified that lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I.<ref name="Lupton">PMID: 34887559 </ref> Mutations to the NF1 gene that prevents the interaction of Neurofibromin with Ras, remove this check on Ras-dependent cell proliferation and uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://en.wikipedia.org/wiki/Neurofibromatosis_type_I Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called [https://en.wikipedia.org/wiki/Caf%C3%A9_au_lait_spot cafe-au-lait macules], clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<ref name="Ratner">PMID:25877329</ref> <br /> <br /> Neurofibromin is also involved in the differentiation of [https://en.wikipedia.org/wiki/Neural_crest neural crest-derived cells], [https://en.wikipedia.org/wiki/Mesenchymal_stem_cell mesenchymal cells], [https://en.wikipedia.org/wiki/Neural_stem_cell neural cells], [https://en.wikipedia.org/wiki/Melanocyte melanocytes], and [https://en.wikipedia.org/wiki/Osteocyte bone cells]. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 point mutations identified to lead to a synthesis of truncated, non-functional protein. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases result from de novo mutations. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations in the NF1 gene have been found in sporadic cancers such as [https://en.wikipedia.org/wiki/Glioblastoma glioblastoma], [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma], [https://en.wikipedia.org/wiki/Lung_cancer lung cancer], [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian cancer], and [https://en.wikipedia.org/wiki/Breast_cancer breast cancer]. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3546611 Sandbox Reserved 1710 2022-04-17T23:28:21Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation [https://www.rcsb.org/structure/7PGR (7PGR)]. The identical chains that make up the dimer are colored lime and cyan. Two important domains in the function of Neurofibromin are highlighted with the GRD colored red and the Sec14-PH domain colored magenta.' scene='90/904315/Closed_spinning/3'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]<br /> Neurofibromin functions as a tumor suppressor protein by associating with [https://proteopedia.org/wiki/index.php/Ras Ras], a protein that signals [https://en.wikipedia.org/wiki/Cell_proliferation cell proliferation] and growth. <ref name="Trovó-Marqui">PMID:16813595</ref> The change in conformation of Neurofibromin from open to closed regulates Ras activity, turning it off, thus stopping cell growth from continuing in excess. Neurofibromin is a dimer made up of two identical monomers consisting of the Sec 14-PH domain and the GRD (Gap-related domain). The orientation of these domains is important for the interaction and binding of Ras to the Arginine finger in Neurofibromin, a key interaction in the regulation of Ras activity. Neurofibromin in its open conformation allows for the Ras association, unlike the closed conformation which is unable to associate with Ras and turn it off. <ref name="Naschberger">PMID:34707296</ref> The closed conformation is stabilized by a triad consisting of Cys 1032, His 1558, and His 1576 and a Zinc atom. The molecular structure and detail of Neurofibromin have been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. Additionally, the structure of Neurofibromin isoform 2 revealed different functional states for the Neurofibromin protein. <ref name="Naschberger">PMID:34707296</ref> Neurofibromin is encoded by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], which is located on chromosome 17. Mutations in the NF1 gene are associated with diseases including Neurofibromatosis Type 1, [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas], and cancers including glioblastoma, neuroblastoma, lung, ovarian, and breast cancer. <ref name="Lupton">PMID: 34887559 </ref> <ref name="Ratner">PMID:25877329</ref> <ref name="Abramowicz">PMID:25182393</ref><br /> <br /> <br /> == Function ==<br /> [[Image:Neurofibromin_Cartoon_Domains.jpg|500 px|left|thumb|Figure 2: Neurofibromin Important Domains in one chain of the homodimer]]<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase] that binds to GTP and hydrolyzes it to GDP. When Ras is active, it subsequently activates other proteins that stimulate cell growth and proliferation. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. Neurofibromin is brought to the membrane to associate with Ras by [https://en.wikipedia.org/wiki/SPRED1 SPRED1]. [https://medlineplus.gov/genetics/gene/spred1/ SPRED1] is a protein that helps regulate the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras/MAPK signaling pathway] responsible for the growth and proliferation of cells. Binding of SPRED1 to [https://en.wikipedia.org/wiki/RAF_kinase Raf] in the MAPK signaling pathway blocks the activation of Raf, halts the rest of the pathway, and stops cell growth and proliferation. Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations. The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg 1276) present in the GRD domain of Neurofibromin. Arg 1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. When Arg 1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division is inhibited. (MECHANISTIC EXPLANATION).<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. The GRD and the Sec14-PH domain are centrally linked by an asymmetric, homodimeric core of four [https://en.wikipedia.org/wiki/Armadillo_repeat ARM] repeats and 27 [https://en.wikipedia.org/wiki/HEAT_repeat HEAT] repeats. The GRD and Sec14-PH domains extend out from the <scene name='90/904315/N-heat_arm/1'>N-HEAT/ARM</scene> core and then return to the <scene name='90/904315/C-heat_arm/1'>C-HEAT/ARM</scene> core. The orientation of the GRD and Sec-14 in relation to the N-HEAT/ARM and C-Heat/ARM determine what conformation neurofibromin is in. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the <scene name='90/904315/Open_conformation/4'>open conformation</scene>.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> == Conformational States ==<br /> <br /> === Closed Conformation ===<br /> In the <scene name='90/904315/Closed/3'>closed, inactive conformation</scene>, the GRD and Sec14-PH domains are rotated so Ras cannot bind. In this conformation, the GRD and Sec14-PH are inaccessible and inactive. Neurofibromin is held in the inactive state by a <scene name='90/904315/Closed_triade/7'>triad</scene> consisting of residues Cys 1032, His 1558, and His 1576 that form a transition metal-binding site with zinc. The rigid organization of the <scene name='90/904315/Closed_triade/8'>triad in closed conformation</scene> keeps the GRD domain packed tightly on top of the Heat Arms in the Neurofibromin core. This tight compaction sterically occludes Neurofibromin from associating with Ras. In its active form, Ras and Neurofibromin will associate via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> (Arg 1276). However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, in the closed conformation, neurofibromin cannot catalyze GTP hydrolysis by Ras and Ras continues to signal for cell growth and proliferation.<br /> <br /> === Open Conformation ===<br /> In the <scene name='90/904315/Open_conformation/4'>open, active conformation</scene>, the GRD and Sec14-PH domain on one protomer have rotated and become accessible for binding to Ras. This transition is initiated by the movement of the transition metal-binding site. The Cys 1032, His 1558, and His 1576 Residues become separated and zinc is not able to bond. In the active form, one protomer has its GRD and Sec14-PH domains oriented oppositely from the inactive form. The GRD rotates -130° and the Sec14-PH domain rotates -90° away from the N-HEAT/ARM. Due to this rotation, Cys 1032 is now located too far away, approximately 30 Å, from His 1558 and His 1576 which results in the loss of the metal-binding site and no formation of the <scene name='90/904315/Open_conformation_triade/6'>triad</scene>. The lack of the transition metal-binding site allows the GRD to orient itself to associate with <scene name='90/904315/Ras_open_conformation/3'>Ras</scene>. This association positions the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> to help stabilize and orient a catalytic Ras residue (Q61) so that the gamma phosphate of GTP can be nucleophilically attacked <ref>PMID:33121128</ref>. When Neurofibromin is in the open, active conformation, Arg 1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:Domain Rotation.jpg|500 px|left|thumb|Figure 3: Rotation of the GRD and Sec14-PH domains from the closed conformation (7PGR) of neurofibromin to the open conformation (7PGT) of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> <br /> <br /> == Disease and Medical Relevance ==<br /> Currently over 1485 mutations of Neurofibromin have been identified that lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I.<ref name="Lupton">PMID: 34887559 </ref> Mutations to the NF1 gene that prevents the interaction of Neurofibromin with Ras, remove this check on Ras-dependent cell proliferation and uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://en.wikipedia.org/wiki/Neurofibromatosis_type_I Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called [https://en.wikipedia.org/wiki/Caf%C3%A9_au_lait_spot cafe-au-lait macules], clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is also involved in the differentiation of [https://en.wikipedia.org/wiki/Neural_crest neural crest-derived cells], [https://en.wikipedia.org/wiki/Mesenchymal_stem_cell mesenchymal cells], [https://en.wikipedia.org/wiki/Neural_stem_cell neural cells], [https://en.wikipedia.org/wiki/Melanocyte melanocytes], and [https://en.wikipedia.org/wiki/Osteocyte bone cells]. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 point mutations identified to lead to a synthesis of truncated, non-functional protein. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases result from de novo mutations. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations in the NF1 gene have been found in sporadic cancers such as [https://en.wikipedia.org/wiki/Glioblastoma glioblastoma], [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma], [https://en.wikipedia.org/wiki/Lung_cancer lung cancer], [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian cancer], and [https://en.wikipedia.org/wiki/Breast_cancer breast cancer]. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3546610 Sandbox Reserved 1710 2022-04-17T23:27:40Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation [https://www.rcsb.org/structure/7PGR (7PGR)]. The identical chains that make up the dimer are colored lime and cyan. Two important domains in the function of Neurofibromin are highlighted with the GRD colored red and the Sec14-PH domain colored magenta.' scene='90/904315/Closed_spinning/3'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]<br /> Neurofibromin functions as a tumor suppressor protein by associating with [https://proteopedia.org/wiki/index.php/Ras Ras], a protein that signals [https://en.wikipedia.org/wiki/Cell_proliferation cell proliferation] and growth. <ref name="Trovó-Marqui">PMID:16813595</ref> The change in conformation of Neurofibromin from open to closed regulates Ras activity, turning it off, thus stopping cell growth from continuing in excess. Neurofibromin is a dimer made up of two identical monomers consisting of the Sec 14-PH domain and the GRD (Gap-related domain). The orientation of these domains is important for the interaction and binding of Ras to the Arginine finger in Neurofibromin, a key interaction in the regulation of Ras activity. Neurofibromin in its open conformation allows for the Ras association, unlike the closed conformation which is unable to associate with Ras and turn it off. <ref name="Naschberger">PMID:34707296</ref> The closed conformation is stabilized by a triad consisting of Cys 1032, His 1558, and His 1576 and a Zinc atom. The molecular structure and detail of Neurofibromin have been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. Additionally, the structure of Neurofibromin isoform 2 revealed different functional states for the Neurofibromin protein. <ref name="Naschberger">PMID:34707296</ref> Neurofibromin is encoded by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], which is located on chromosome 17. Mutations in the NF1 gene are associated with diseases including Neurofibromatosis Type 1, [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas], and cancers including glioblastoma, neuroblastoma, lung, ovarian, and breast cancer. <ref name="Lupton">PMID: 34887559 </ref> <ref name="Ratner">PMID:25877329</ref></ref> <ref name="Abramowicz">PMID:25182393</ref><br /> <br /> <br /> == Function ==<br /> [[Image:Neurofibromin_Cartoon_Domains.jpg|500 px|left|thumb|Figure 2: Neurofibromin Important Domains in one chain of the homodimer]]<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase] that binds to GTP and hydrolyzes it to GDP. When Ras is active, it subsequently activates other proteins that stimulate cell growth and proliferation. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. Neurofibromin is brought to the membrane to associate with Ras by [https://en.wikipedia.org/wiki/SPRED1 SPRED1]. [https://medlineplus.gov/genetics/gene/spred1/ SPRED1] is a protein that helps regulate the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras/MAPK signaling pathway] responsible for the growth and proliferation of cells. Binding of SPRED1 to [https://en.wikipedia.org/wiki/RAF_kinase Raf] in the MAPK signaling pathway blocks the activation of Raf, halts the rest of the pathway, and stops cell growth and proliferation. Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations. The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg 1276) present in the GRD domain of Neurofibromin. Arg 1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. When Arg 1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division is inhibited. (MECHANISTIC EXPLANATION).<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. The GRD and the Sec14-PH domain are centrally linked by an asymmetric, homodimeric core of four [https://en.wikipedia.org/wiki/Armadillo_repeat ARM] repeats and 27 [https://en.wikipedia.org/wiki/HEAT_repeat HEAT] repeats. The GRD and Sec14-PH domains extend out from the <scene name='90/904315/N-heat_arm/1'>N-HEAT/ARM</scene> core and then return to the <scene name='90/904315/C-heat_arm/1'>C-HEAT/ARM</scene> core. The orientation of the GRD and Sec-14 in relation to the N-HEAT/ARM and C-Heat/ARM determine what conformation neurofibromin is in. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the <scene name='90/904315/Open_conformation/4'>open conformation</scene>.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> == Conformational States ==<br /> <br /> === Closed Conformation ===<br /> In the <scene name='90/904315/Closed/3'>closed, inactive conformation</scene>, the GRD and Sec14-PH domains are rotated so Ras cannot bind. In this conformation, the GRD and Sec14-PH are inaccessible and inactive. Neurofibromin is held in the inactive state by a <scene name='90/904315/Closed_triade/7'>triad</scene> consisting of residues Cys 1032, His 1558, and His 1576 that form a transition metal-binding site with zinc. The rigid organization of the <scene name='90/904315/Closed_triade/8'>triad in closed conformation</scene> keeps the GRD domain packed tightly on top of the Heat Arms in the Neurofibromin core. This tight compaction sterically occludes Neurofibromin from associating with Ras. In its active form, Ras and Neurofibromin will associate via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> (Arg 1276). However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, in the closed conformation, neurofibromin cannot catalyze GTP hydrolysis by Ras and Ras continues to signal for cell growth and proliferation.<br /> <br /> === Open Conformation ===<br /> In the <scene name='90/904315/Open_conformation/4'>open, active conformation</scene>, the GRD and Sec14-PH domain on one protomer have rotated and become accessible for binding to Ras. This transition is initiated by the movement of the transition metal-binding site. The Cys 1032, His 1558, and His 1576 Residues become separated and zinc is not able to bond. In the active form, one protomer has its GRD and Sec14-PH domains oriented oppositely from the inactive form. The GRD rotates -130° and the Sec14-PH domain rotates -90° away from the N-HEAT/ARM. Due to this rotation, Cys 1032 is now located too far away, approximately 30 Å, from His 1558 and His 1576 which results in the loss of the metal-binding site and no formation of the <scene name='90/904315/Open_conformation_triade/6'>triad</scene>. The lack of the transition metal-binding site allows the GRD to orient itself to associate with <scene name='90/904315/Ras_open_conformation/3'>Ras</scene>. This association positions the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> to help stabilize and orient a catalytic Ras residue (Q61) so that the gamma phosphate of GTP can be nucleophilically attacked <ref>PMID:33121128</ref>. When Neurofibromin is in the open, active conformation, Arg 1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:Domain Rotation.jpg|500 px|left|thumb|Figure 3: Rotation of the GRD and Sec14-PH domains from the closed conformation (7PGR) of neurofibromin to the open conformation (7PGT) of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> <br /> <br /> == Disease and Medical Relevance ==<br /> Currently over 1485 mutations of Neurofibromin have been identified that lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I.<ref name="Lupton">PMID: 34887559 </ref> Mutations to the NF1 gene that prevents the interaction of Neurofibromin with Ras, remove this check on Ras-dependent cell proliferation and uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://en.wikipedia.org/wiki/Neurofibromatosis_type_I Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called [https://en.wikipedia.org/wiki/Caf%C3%A9_au_lait_spot cafe-au-lait macules], clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is also involved in the differentiation of [https://en.wikipedia.org/wiki/Neural_crest neural crest-derived cells], [https://en.wikipedia.org/wiki/Mesenchymal_stem_cell mesenchymal cells], [https://en.wikipedia.org/wiki/Neural_stem_cell neural cells], [https://en.wikipedia.org/wiki/Melanocyte melanocytes], and [https://en.wikipedia.org/wiki/Osteocyte bone cells]. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 point mutations identified to lead to a synthesis of truncated, non-functional protein. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases result from de novo mutations. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations in the NF1 gene have been found in sporadic cancers such as [https://en.wikipedia.org/wiki/Glioblastoma glioblastoma], [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma], [https://en.wikipedia.org/wiki/Lung_cancer lung cancer], [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian cancer], and [https://en.wikipedia.org/wiki/Breast_cancer breast cancer]. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3546601 Sandbox Reserved 1710 2022-04-17T23:20:58Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation [https://www.rcsb.org/structure/7PGR (7PGR)]. The identical chains that make up the dimer are colored lime and cyan. Two important domains in the function of Neurofibromin are highlighted with the GRD colored red and the Sec14-PH domain colored magenta.' scene='90/904315/Closed_spinning/3'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]<br /> Neurofibromin is encoded by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], which is located on chromosome 17. Neurofibromin functions as a tumor suppressor protein by associating with [https://proteopedia.org/wiki/index.php/Ras Ras], a protein that signals [https://en.wikipedia.org/wiki/Cell_proliferation cell proliferation] and growth. <ref name="Trovó-Marqui">PMID:16813595</ref> The change in conformation of Neurofibromin from open to closed regulates Ras activity, turning it off, thus stopping cell growth from continuing in excess. Neurofibromin is a dimer made up of two identical monomers consisting of the Sec 14-PH domain and the GRD (Gap-related domain). The orientation of these domains is important for the interaction and binding of Ras to the Arginine finger in Neurofibromin, a key interaction in the regulation of Ras activity. Neurofibromin in its open conformation allows for the Ras association, unlike the closed conformation which is unable to associate with Ras and turn it off. <ref name="Naschberger">PMID:34707296</ref> The closed conformation is stabilized by a triad consisting of Cys 1032, His 1558, and His 1576 and a Zinc atom. The molecular structure and detail of Neurofibromin have been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. Additionally, the structure of Neurofibromin isoform 2 revealed different functional states for the Neurofibromin protein. <ref name="Naschberger">PMID:34707296</ref> Mutations in the NF1 gene are associated with diseases including Neurofibromatosis Type 1, [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas], and cancers including glioblastoma, neuroblastoma, lung, ovarian, and breast cancer. <ref name="Lupton">PMID: 34887559 </ref> <ref name="Ratner">PMID:25877329</ref> <ref name="Abramowicz">PMID:25182393</ref><br /> <br /> <br /> == Function ==<br /> [[Image:Neurofibromin_Cartoon_Domains.jpg|500 px|left|thumb|Figure 2: Neurofibromin Important Domains in one chain of the homodimer]]<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase] that binds to GTP and hydrolyzes it to GDP. When Ras is active, it subsequently activates other proteins that stimulate cell growth and proliferation. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. Neurofibromin is brought to the membrane to associate with Ras by [https://en.wikipedia.org/wiki/SPRED1 SPRED1]. [https://medlineplus.gov/genetics/gene/spred1/ SPRED1] is a protein that helps regulate the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras/MAPK signaling pathway] responsible for the growth and proliferation of cells. Binding of SPRED1 to [https://en.wikipedia.org/wiki/RAF_kinase Raf] in the MAPK signaling pathway blocks the activation of Raf, halts the rest of the pathway, and stops cell growth and proliferation. Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations. The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg 1276) present in the GRD domain of Neurofibromin. Arg 1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. When Arg 1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division is inhibited. (MECHANISTIC EXPLANATION).<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. The GRD and the Sec14-PH domain are centrally linked by an asymmetric, homodimeric core of four [https://en.wikipedia.org/wiki/Armadillo_repeat ARM] repeats and 27 [https://en.wikipedia.org/wiki/HEAT_repeat HEAT] repeats. The GRD and Sec14-PH domains extend out from the <scene name='90/904315/N-heat_arm/1'>N-HEAT/ARM</scene> core and then return to the <scene name='90/904315/C-heat_arm/1'>C-HEAT/ARM</scene> core. The orientation of the GRD and Sec-14 in relation to the N-HEAT/ARM and C-Heat/ARM determine what conformation neurofibromin is in. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the <scene name='90/904315/Open_conformation/4'>open conformation</scene>.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> == Conformational States ==<br /> <br /> === Closed Conformation ===<br /> In the <scene name='90/904315/Closed/3'>closed, inactive conformation</scene>, the GRD and Sec14-PH domains are rotated so Ras cannot bind. In this conformation, the GRD and Sec14-PH are inaccessible and inactive. Neurofibromin is held in the inactive state by a <scene name='90/904315/Closed_triade/7'>triad</scene> consisting of residues Cys 1032, His 1558, and His 1576 that form a transition metal-binding site with zinc. The rigid organization of the <scene name='90/904315/Closed_triade/8'>triad in closed conformation</scene> keeps the GRD domain packed tightly on top of the Heat Arms in the Neurofibromin core. This tight compaction sterically occludes Neurofibromin from associating with Ras. In its active form, Ras and Neurofibromin will associate via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> (Arg 1276). However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, in the closed conformation, neurofibromin cannot catalyze GTP hydrolysis by Ras and Ras continues to signal for cell growth and proliferation.<br /> <br /> === Open Conformation ===<br /> In the <scene name='90/904315/Open_conformation/4'>open, active conformation</scene>, the GRD and Sec14-PH domain on one protomer have rotated and become accessible for binding to Ras. This transition is initiated by the movement of the transition metal-binding site. The Cys 1032, His 1558, and His 1576 Residues become separated and zinc is not able to bond. In the active form, one protomer has its GRD and Sec14-PH domains oriented oppositely from the inactive form. The GRD rotates -130° and the Sec14-PH domain rotates -90° away from the N-HEAT/ARM. Due to this rotation, Cys 1032 is now located too far away, approximately 30 Å, from His 1558 and His 1576 which results in the loss of the metal-binding site and no formation of the <scene name='90/904315/Open_conformation_triade/6'>triad</scene>. The lack of the transition metal-binding site allows the GRD to orient itself to associate with <scene name='90/904315/Ras_open_conformation/3'>Ras</scene>. This association positions the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> to help stabilize and orient a catalytic Ras residue (Q61) so that the gamma phosphate of GTP can be nucleophilically attacked <ref>PMID:33121128</ref>. When Neurofibromin is in the open, active conformation, Arg 1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:Domain Rotation.jpg|500 px|left|thumb|Figure 3: Rotation of the GRD and Sec14-PH domains from the closed conformation (7PGR) of neurofibromin to the open conformation (7PGT) of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> <br /> <br /> == Disease and Medical Relevance ==<br /> Currently over 1485 mutations of Neurofibromin have been identified that lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I.<ref name="Lupton">PMID: 34887559 </ref> Mutations to the NF1 gene that prevents the interaction of Neurofibromin with Ras, remove this check on Ras-dependent cell proliferation and uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://en.wikipedia.org/wiki/Neurofibromatosis_type_I Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called [https://en.wikipedia.org/wiki/Caf%C3%A9_au_lait_spot cafe-au-lait macules], clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is also involved in the differentiation of [https://en.wikipedia.org/wiki/Neural_crest neural crest-derived cells], [https://en.wikipedia.org/wiki/Mesenchymal_stem_cell mesenchymal cells], [https://en.wikipedia.org/wiki/Neural_stem_cell neural cells], [https://en.wikipedia.org/wiki/Melanocyte melanocytes], and [https://en.wikipedia.org/wiki/Osteocyte bone cells]. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 point mutations identified to lead to a synthesis of truncated, non-functional protein. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases result from de novo mutations. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations in the NF1 gene have been found in sporadic cancers such as [https://en.wikipedia.org/wiki/Glioblastoma glioblastoma], [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma], [https://en.wikipedia.org/wiki/Lung_cancer lung cancer], [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian cancer], and [https://en.wikipedia.org/wiki/Breast_cancer breast cancer]. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3546582 Sandbox Reserved 1710 2022-04-17T23:11:23Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation [https://www.rcsb.org/structure/7PGR (7PGR)]. The identical chains that make up the dimer are colored lime and cyan. Two important domains in the function of Neurofibromin are highlighted with the GRD colored red and the Sec14-PH domain colored magenta.' scene='90/904315/Closed_spinning/3'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]<br /> Neurofibromin is encoded by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], which is located on chromosome 17. Neurofibromin functions as a tumor suppressor protein by associating with [https://proteopedia.org/wiki/index.php/Ras Ras], a protein that signals [https://en.wikipedia.org/wiki/Cell_proliferation cell proliferation] and growth. <ref name="Trovó-Marqui">PMID:16813595</ref> The change in conformation of Neurofibromin from open to closed regulates Ras activity, turning it off, thus stopping cell growth from continuing in excess. Neurofibromin is a dimer made up of two identical monomers consisting of the Sec 14-PH domain and the GRD (Gap-related domain). The orientation of these domain are important for the interaction and binding of Ras to the Arginine finger in Neurofibromin, a key interaction in the regulation of Ras activity. Neurofibromin in its open conformation allows for the Ras association, unlike the closed conformation which is unable to associate with Ras and turn it off. <ref name="Naschberger">PMID:34707296</ref> The closed conformation is stabilized by a triad consisting of Cys 1032, His 1558, and His 1576 and a Zinc atom. The molecular structure and detail of Neurofibromin have been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. Additionally, the structure of Neurofibromin isoform 2 revealed different functional states for the Neurofibromin protein. <ref name="Naschberger">PMID:34707296</ref> Mutations in the NF1 gene are associated with diseases including Neurofibromatosis Type 1, [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas], and cancers including glioblastoma, neuroblastoma, lung, ovarian, and breast cancer. <ref name="Lupton">PMID: 34887559 </ref> <ref name="Ratner">PMID:25877329</ref><br /> <br /> <br /> == Function ==<br /> [[Image:Neurofibromin_Cartoon_Domains.jpg|500 px|left|thumb|Figure 2: Neurofibromin Important Domains in one chain of the homodimer]]<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase] that binds to GTP and hydrolyzes it to GDP. When Ras is active, it subsequently activates other proteins that stimulate cell growth and proliferation. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. Neurofibromin is brought to the membrane to associate with Ras by [https://en.wikipedia.org/wiki/SPRED1 SPRED1]. [https://medlineplus.gov/genetics/gene/spred1/ SPRED1] is a protein that helps regulate the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras/MAPK signaling pathway] responsible for the growth and proliferation of cells. Binding of SPRED1 to [https://en.wikipedia.org/wiki/RAF_kinase Raf] in the MAPK signaling pathway blocks the activation of Raf, halts the rest of the pathway, and stops cell growth and proliferation. Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations. The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg 1276) present in the GRD domain of Neurofibromin. Arg 1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. When Arg 1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division is inhibited. (MECHANISTIC EXPLANATION).<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. The GRD and the Sec14-PH domain are centrally linked by an asymmetric, homodimeric core of four [https://en.wikipedia.org/wiki/Armadillo_repeat ARM] repeats and 27 [https://en.wikipedia.org/wiki/HEAT_repeat HEAT] repeats. The GRD and Sec14-PH domains extend out from the <scene name='90/904315/N-heat_arm/1'>N-HEAT/ARM</scene> core and then return to the <scene name='90/904315/C-heat_arm/1'>C-HEAT/ARM</scene> core. The orientation of the GRD and Sec-14 in relation to the N-HEAT/ARM and C-Heat/ARM determine what conformation neurofibromin is in. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the <scene name='90/904315/Open_conformation/4'>open conformation</scene>.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> == Conformational States ==<br /> <br /> === Closed Conformation ===<br /> In the <scene name='90/904315/Closed/3'>closed, inactive conformation</scene>, the GRD and Sec14-PH domains are rotated so Ras cannot bind. In this conformation, the GRD and Sec14-PH are inaccessible and inactive. Neurofibromin is held in the inactive state by a <scene name='90/904315/Closed_triade/7'>triad</scene> consisting of residues Cys 1032, His 1558, and His 1576 that form a transition metal-binding site with zinc. The rigid organization of the <scene name='90/904315/Closed_triade/8'>triad in closed conformation</scene> keeps the GRD domain packed tightly on top of the Heat Arms in the Neurofibromin core. This tight compaction sterically occludes Neurofibromin from associating with Ras. In its active form, Ras and Neurofibromin will associate via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> (Arg 1276). However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, in the closed conformation, neurofibromin cannot catalyze GTP hydrolysis by Ras and Ras continues to signal for cell growth and proliferation.<br /> <br /> === Open Conformation ===<br /> In the <scene name='90/904315/Open_conformation/4'>open, active conformation</scene>, the GRD and Sec14-PH domain on one protomer have rotated and become accessible for binding to Ras. This transition is initiated by the movement of the transition metal-binding site. The Cys 1032, His 1558, and His 1576 Residues become separated and zinc is not able to bond. In the active form, one protomer has its GRD and Sec14-PH domains oriented oppositely from the inactive form. The GRD rotates -130° and the Sec14-PH domain rotates -90° away from the N-HEAT/ARM. Due to this rotation, Cys 1032 is now located too far away, approximately 30 Å, from His 1558 and His 1576 which results in the loss of the metal-binding site and no formation of the <scene name='90/904315/Open_conformation_triade/6'>triad</scene>. The lack of the transition metal-binding site allows the GRD to orient itself to associate with <scene name='90/904315/Ras_open_conformation/3'>Ras</scene>. This association positions the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> to help stabilize and orient a catalytic Ras residue (Q61) so that the gamma phosphate of GTP can be nucleophilically attacked <ref>PMID:33121128</ref>. When Neurofibromin is in the open, active conformation, Arg 1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:Domain Rotation.jpg|500 px|left|thumb|Figure 3: Rotation of the GRD and Sec14-PH domains from the closed conformation (7PGR) of neurofibromin to the open conformation (7PGT) of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> <br /> <br /> == Disease and Medical Relevance ==<br /> Currently over 1485 mutations of Neurofibromin have been identified that lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I.<ref name="Lupton">PMID: 34887559 </ref> Mutations to the NF1 gene that prevents the interaction of Neurofibromin with Ras, remove this check on Ras-dependent cell proliferation and uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://en.wikipedia.org/wiki/Neurofibromatosis_type_I Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called [https://en.wikipedia.org/wiki/Caf%C3%A9_au_lait_spot cafe-au-lait macules], clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is also involved in the differentiation of [https://en.wikipedia.org/wiki/Neural_crest neural crest-derived cells], [https://en.wikipedia.org/wiki/Mesenchymal_stem_cell mesenchymal cells], [https://en.wikipedia.org/wiki/Neural_stem_cell neural cells], [https://en.wikipedia.org/wiki/Melanocyte melanocytes], and [https://en.wikipedia.org/wiki/Osteocyte bone cells]. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 point mutations identified to lead to a synthesis of truncated, non-functional protein. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases result from de novo mutations. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations in the NF1 gene have been found in sporadic cancers such as [https://en.wikipedia.org/wiki/Glioblastoma glioblastoma], [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma], [https://en.wikipedia.org/wiki/Lung_cancer lung cancer], [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian cancer], and [https://en.wikipedia.org/wiki/Breast_cancer breast cancer]. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3546559 Sandbox Reserved 1710 2022-04-17T22:51:36Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation [https://www.rcsb.org/structure/7PGR (7PGR)]. The identical chains that make up the dimer are colored lime and cyan. Two important domains in the function of Neurofibromin are highlighted with the GRD colored red and the Sec14-PH domain colored magenta.' scene='90/904315/Closed_spinning/3'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]<br /> Neurofibromin is encoded by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], which is located on chromosome 17. Neurofibromin functions as a tumor suppressor protein by associating with [https://proteopedia.org/wiki/index.php/Ras Ras], a protein that signals [https://en.wikipedia.org/wiki/Cell_proliferation cell proliferation] and growth. <ref name="Trovó-Marqui">PMID:16813595</ref> The change in conformation of Neurofibromin from open to closed regulates Ras activity, turning it off, thus stopping cell growth from continuing in excess. Neurofibromin is a dimer made up of two identical monomers consisting of the Sec 14-PH domain and the GRD (Gap-related domain). The orientation of these domain are important for the interaction and binding of Ras to the Arginine finger in Neurofibromin, a key interaction in the regulation of Ras activity. Neurofibromin in its open conformation allows for the Ras association, unlike the closed conformation which is unable to associate with Ras and turn it off. <ref name="Naschberger">PMID:34707296</ref> The closed conformation is stabilized by a triad consisting of Cys 1032, His 1558, and His 1576 and a Zinc atom. The molecular structure and detail of Neurofibromin have been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. Additionally, the structure of Neurofibromin isoform 2 revealed different functional states for the Neurofibromin protein. <ref name="Naschberger">PMID:34707296</ref> Mutations in the NF1 gene are associated with diseases including Neurofibromatosis Type 1, [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas], and cancers including glioblastoma, neuroblastoma, lung, ovarian, and breast cancer. <ref name="Lupton">PMID: 34887559 </ref> <ref name="Ratner">PMID:25877329</ref><br /> <br /> <br /> == Function ==<br /> [[Image:Neurofibromin_Cartoon_Domains.jpg|500 px|left|thumb|Figure 2: Neurofibromin Important Domains in one chain of the homodimer]]<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase] that binds to GTP and hydrolyzes it to GDP. When Ras is active, it subsequently activates other proteins that stimulate cell growth and proliferation. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. Neurofibromin is brought to the membrane to associate with Ras by [https://en.wikipedia.org/wiki/SPRED1 SPRED1]. [https://medlineplus.gov/genetics/gene/spred1/ SPRED1] is a protein that helps regulate the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras/MAPK signaling pathway] responsible for the growth and proliferation of cells. Binding of SPRED1 to [https://en.wikipedia.org/wiki/RAF_kinase Raf] in the MAPK signaling pathway blocks the activation of Raf, halts the rest of the pathway, and stops cell growth and proliferation. Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations. The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg 1276) present in the GRD domain of Neurofibromin. Arg 1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. When Arg 1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division is inhibited. (MECHANISTIC EXPLANATION).<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. The GRD and the Sec14-PH domain are centrally linked by an asymmetric, homodimeric core of four [https://en.wikipedia.org/wiki/Armadillo_repeat ARM] repeats and 27 [https://en.wikipedia.org/wiki/HEAT_repeat HEAT] repeats. The GRD and Sec14-PH domains extend out from the <scene name='90/904315/N-heat_arm/1'>N-HEAT/ARM</scene> core and then return to the <scene name='90/904315/C-heat_arm/1'>C-HEAT/ARM</scene> core. The orientation of the GRD and Sec-14 in relation to the N-HEAT/ARM and C-Heat/ARM determine what conformation neurofibromin is in. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the <scene name='90/904315/Open_conformation/4'>open conformation</scene>.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> == Conformational States ==<br /> <br /> === Closed Conformation ===<br /> In the <scene name='90/904315/Closed/3'>closed, inactive conformation</scene>, the GRD and Sec14-PH domains are rotated so Ras cannot bind. In this conformation, the GRD and Sec14-PH are inaccessible and inactive. Neurofibromin is held in the inactive state by a <scene name='90/904315/Closed_triade/7'>triad</scene> consisting of residues Cys 1032, His 1558, and His 1576 that form a transition metal-binding site with zinc. The rigid organization of the <scene name='90/904315/Closed_triade/8'>triad in closed conformation</scene> keeps the GRD domain packed tightly on top of the Heat Arms in the Neurofibromin core. This tight compaction sterically occludes Neurofibromin from associating with Ras. In its active form, Ras and Neurofibromin will associate via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> (Arg 1276). However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, in the closed conformation, neurofibromin cannot catalyze GTP hydrolysis by Ras and Ras continues to signal for cell growth and proliferation.<br /> <br /> === Open Conformation ===<br /> In the <scene name='90/904315/Open_conformation/4'>open, active conformation</scene>, the GRD and Sec14-PH domain on one protomer have rotated and become accessible for binding to Ras. This transition is initiated by the movement of the transition metal-binding site. The Cys 1032, His 1558, and His 1576 Residues become separated and zinc is not able to bond. In the active form, one protomer has its GRD and Sec14-PH domains oriented oppositely from the inactive form. The GRD rotates -130° and the Sec14-PH domain rotates -90° away from the N-HEAT/ARM. Due to this rotation, Cys 1032 is now located too far away, approximately 30 Å, from His 1558 and His 1576 which results in the loss of the metal-binding site and no formation of the <scene name='90/904315/Open_conformation_triade/6'>triad</scene>. The lack of the transition metal-binding site allows the GRD to orient itself to associate with <scene name='90/904315/Ras_open_conformation/3'>Ras</scene>. This association positions the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> to help stabilize and orient a catalytic Ras residue (Q61) so that the gamma phosphate of GTP can be nucleophilically attackedxxxx. When Neurofibromin is in the open, active conformation, Arg 1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:Domain Rotation.jpg|500 px|left|thumb|Figure 3: Rotation of the GRD and Sec14-PH domains from the closed conformation (7PGR) of neurofibromin to the open conformation (7PGT) of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> <br /> <br /> == Disease and Medical Relevance ==<br /> Currently over 1485 mutations of Neurofibromin have been identified that lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I.<ref name="Lupton">PMID: 34887559 </ref> Mutations to the NF1 gene that prevents the interaction of Neurofibromin with Ras, remove this check on Ras-dependent cell proliferation and uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://en.wikipedia.org/wiki/Neurofibromatosis_type_I Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called [https://en.wikipedia.org/wiki/Caf%C3%A9_au_lait_spot cafe-au-lait macules], clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is also involved in the differentiation of [https://en.wikipedia.org/wiki/Neural_crest neural crest-derived cells], [https://en.wikipedia.org/wiki/Mesenchymal_stem_cell mesenchymal cells], [https://en.wikipedia.org/wiki/Neural_stem_cell neural cells], [https://en.wikipedia.org/wiki/Melanocyte melanocytes], and [https://en.wikipedia.org/wiki/Osteocyte bone cells]. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 point mutations identified lead to a synthesis of truncated, non-functional protein. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases result from de novo mutations. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations in the NF1 gene have been found in sporadic cancers such as [https://en.wikipedia.org/wiki/Glioblastoma glioblastoma], [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma], [https://en.wikipedia.org/wiki/Lung_cancer lung cancer], [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian cancer], and [https://en.wikipedia.org/wiki/Breast_cancer breast cancer]. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3543125 Sandbox Reserved 1710 2022-04-12T20:10:34Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation [https://www.rcsb.org/structure/7PGR (7PGR)]. The identical chains that make up the dimer are colored lime and cyan. Two important domains in the function of Neurofibromin are highlighted with the GRD colored red and the Sec14-PH domain colored magenta.' scene='90/904315/Closed_spinning/3'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]<br /> Neurofibromin functions as a tumor suppressor protein by associating with [https://proteopedia.org/wiki/index.php/Ras Ras], a protein that signals cell proliferation and growth. <ref name="Trovó-Marqui">PMID:16813595</ref> The change in conformation of Neurofibromin from open to closed regulates Ras activity, turning it off, thus stopping cell growth from continuing in excess. Neurofibromin is a dimer made up of two identical monomers. On each monomer, there are domains Sec 14-PH (Section 14-ph domain) and GRD (Gap-related domain) whose orientations are important for the interaction and binding of Ras to the Arginine finger, which is key in the regulation of Ras activity. Neurofibromin in its open conformation allows for the Ras association, unlike the closed conformation which is unable to associate with Ras and turn it off. <ref name="Naschberger">PMID:34707296</ref> This closed conformation is stabilized by the strong interactions between a triad of C1032, H1558, and H1576, water, and a Zn atom. The molecular structure and detail of Neurofibromin have been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. Additionally, the structure of Neurofibromin isoform 2 revealed different functional states for the Neurofibromin protein. <ref name="Naschberger">PMID:34707296</ref> Neurofibromin is encoded by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], which is located on chromosome 17. Mutations in the NF1 gene are associated with diseases including Neurofibromatosis Type 1, [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas], and cancers including glioblastoma, neuroblastoma, lung, ovarian, and breast cancer. <ref name="Lupton">PMID: 34887559 </ref> <ref name="Ratner">PMID:25877329</ref><br /> <br /> <br /> == Function ==<br /> [[Image:Neurofibromin_Cartoon_Domains.jpg|500 px|left|thumb|Figure 2: Neurofibromin Important Domains in one chain of the homodimer]]<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase] that binds to GTP and hydrolyzes it to GDP. When Ras is active, it subsequently activates other proteins that stimulate cell growth and proliferation. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. Neurofibromin is brought to the membrane to associate with Ras by [https://en.wikipedia.org/wiki/SPRED1 SPRED1]. [https://medlineplus.gov/genetics/gene/spred1/ SPRED1] is a protein that helps regulate the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras/MAPK signaling pathway] responsible for the growth and proliferation of cells. Binding of SPRED1 to [https://en.wikipedia.org/wiki/RAF_kinase Raf] in the MAPK signaling pathway blocks the activation of Raf, halts the rest of the pathway, and stops cell growth and proliferation. Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations. The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg 1276) present in the GRD domain of Neurofibromin. Arg 1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. When Arg 1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division are inhibited. (MECHANISTIC EXPLANATION).<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. The GRD and the Sec14-PH domain are centrally linked by an asymmetric, homodimeric core of four [https://en.wikipedia.org/wiki/Armadillo_repeat ARM] repeats and 27 [https://en.wikipedia.org/wiki/HEAT_repeat HEAT] repeats. The GRD and Sec14-PH domains extend out from the <scene name='90/904315/N-heat_arm/1'>N-HEAT/ARM</scene> core and then return to the <scene name='90/904315/C-heat_arm/1'>C-HEAT/ARM</scene> core. The orientation of the GRD and Sec-14 in relation to the N-HEAT/ARM and C-Heat/ARM determine what conformation neurofibromin is in. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the <scene name='90/904315/Open_conformation/4'>open conformation</scene>.<ref name="Naschberger">PMID:34707296</ref><br /> <br /> == Conformational States ==<br /> <br /> === Closed Conformation ===<br /> In the <scene name='90/904315/Closed/3'>closed, inactive conformation</scene>, the GRD and Sec14-PH domains are rotated so Ras cannot bind. In this conformation, the GRD and Sec14-PH are inaccessible and inactive. Neurofibromin is held in the inactive state by a <scene name='90/904315/Closed_triade/7'>triad</scene> consisting of residues Cys 1032, His 1558, and His 1576 that form a transition metal-binding site with zinc. The rigid organization of the <scene name='90/904315/Closed_triade/8'>triad in closed conformation</scene> keeps the GRD domain packed tightly on top of the Heat Arms in the Neurofibromin core. This tight compaction sterically occludes Neurofibromin from associating with Ras. In its active form, Ras and Neurofibromin will associate via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> (Arg 1276). However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, in the closed conformation, neurofibromin cannot catalyze GTP hydrolysis by Ras and Ras continues to signal for cell growth and proliferation.<br /> <br /> === Open Conformation ===<br /> In the <scene name='90/904315/Open_conformation/4'>open, active conformation</scene>, (REWRITE ABOUT RAS REGULATION)<br /> <br /> This transition is initiated by movement of the transition metal-binding site. The Cys 1032, His 1558, and His 1576 Residues become separated and zinc is not able to bond. In the active form, one protomer has its GRD and Sec14-PH domains oriented oppositely from the inactive form. The GRD rotates -130° and the Sec14-PH domain rotates -90° away from the N-HEAT/ARM. Due to this rotation, Cys 1032 is now located too far away, approximately 30 Å, from His 1558 and His 1576 which results in the loss of the metal-binding site and no formation of the <scene name='90/904315/Open_conformation_triade/6'>triad</scene>. The lack of the transition metal-binding site allows the GRD to orient itself to associate with <scene name='90/904315/Ras_open_conformation/3'>Ras</scene>. This association positions the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> (TO DO WHAT?). When Neurofibromin is in the open, active conformation, Arg 1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:Domain Rotation.jpg|500 px|left|thumb|Figure 3: Rotation of the GRD and Sec14-PH domains from the closed conformation (7PGR) of neurofibromin to the open conformation (7PGT) of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> <br /> <br /> == Disease and Medical Relevance ==<br /> Currently over 1485 mutations of Neurofibromin have been identified that lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I.<ref name="Lupton">PMID: 34887559 </ref> Mutations to the NF1 gene that prevent the interaction of Neurofibromin with Ras, remove this check on Ras-dependent cell proliferation and uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://en.wikipedia.org/wiki/Neurofibromatosis_type_I Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called [https://en.wikipedia.org/wiki/Caf%C3%A9_au_lait_spot cafe-au-lait macules], clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is also involved in the differentiation of [https://en.wikipedia.org/wiki/Neural_crest neural crest-derived cells], [https://en.wikipedia.org/wiki/Mesenchymal_stem_cell mesenchymal cells], [https://en.wikipedia.org/wiki/Neural_stem_cell neural cells], [https://en.wikipedia.org/wiki/Melanocyte melanocytes], and [https://en.wikipedia.org/wiki/Osteocyte bone cells]. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 point mutations identified lead to a synthesis of truncated, non-functional protein. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases result from de novo mutations. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations in the NF1 gene have been found in sporadic cancers such as [https://en.wikipedia.org/wiki/Glioblastoma glioblastoma], [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma], [https://en.wikipedia.org/wiki/Lung_cancer lung cancer], [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian cancer], and [https://en.wikipedia.org/wiki/Breast_cancer breast cancer]. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3543012 Sandbox Reserved 1710 2022-04-12T17:39:45Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation [https://www.rcsb.org/structure/7PGR (7PGR)]. The identical chains that make up the dimer are colored lime and cyan. Two important domains in the function of Neurofibromin are highlighted with the GRD colored red and the Sec14-PH domain colored magenta.' scene='90/904315/Closed_spinning/3'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin Surface w Labels.jpg|500 px|right|thumb|Figure 1: Surface Rendering of Neurofibromin in its Open (7PGT) and Closed (7PGR) Conformation.]]<br /> Neurofibromin is encoded by [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 gene], located on chromosome 17. Neurofibromin functions as a tumor suppressor through its association with the protein [https://proteopedia.org/wiki/index.php/Ras Ras]. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin are associated with diseases such as [https://en.wikipedia.org/wiki/Neurofibroma Plexiform Neurofibromas]. (FLESH OUT INTRODUCTION)<br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> <br /> == Function ==<br /> [[Image:Neurofibromin_Cartoon_Domains.jpg|500 px|left|thumb|Figure 2: Neurofibromin Important Domains in one chain of the homodimer]]<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> It prevents cell growth by turning off [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a small, monomeric [https://en.wikipedia.org/wiki/GTPase GTPase]. Ras is membrane-bound and interacts with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. (DEFINE RAS) Neurofibromin is brought to the membrane to associate with Ras by [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. (DEFINE SPRED1) Unlike Ras, Neurofibromin can interact with SPRED1 in both the open and closed conformations. The interaction between Neurofibromin and Ras is activated via an [https://en.wikipedia.org/wiki/Arginine_finger Arginine finger] (Arg 1276) present in the GRD domain of Neurofibromin. Arg 1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation. When Arg 1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by speeding up Ras's GTPase activity, hydrolyzing the GTP associated with Ras to GDP. In its GDP bound state, Ras is inactive and cell growth and division are inhibited. (MECHANISTIC EXPLANATION).<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/5'>homodimer</scene> made up of two identical chains. Neurofibromin has two conformations, open and closed. Shifting between these controls neurofibromin's ability to associate with Ras and perform its function of Ras regulation. The transformation between the overall closed and open conformations transitions it from an active to inactive state. There are <scene name='90/904315/Sec14ph_and_grd_domain/1'>two important domains</scene> involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer has its GRD and Sec14-PH domains rotated into the open conformation.<br /> <br /> <scene name='90/904315/N-heat_arm/1'>N-HEAT/ARM</scene><br /> <scene name='90/904315/C-heat_arm/1'>C-HEAT/ARM</scene><br /> == Conformational States ==<br /> <br /> === Closed Conformation ===<br /> In the <scene name='90/904315/Closed/3'>closed, inactive conformation</scene>, the GRD and Sec14-PH domains are rotated so Ras cannot bind. In this conformation, the GRD and Sec14-PH are inaccessible and inactive. Neurofibromin is held in the inactive state by a <scene name='90/904315/Closed_triade/2'>triad</scene> consisting of residues Cys 1032, His 1558, and His 1576 that form a transition metal-binding site with zinc. The rigid organization of the <scene name='90/904315/Catalytic_triade/3'>triad in closed conformation</scene> keeps the GRD domain packed tightly on top of the Heat Arms in the Neurofibromin core. This tight compaction sterically occludes Neurofibromin from associating with Ras. In its active form, Ras and Neurofibromin will associate via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> (Arg 1276). However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, in the closed conformation, neurofibromin cannot catalyze GTP hydrolysis by Ras and Ras continues to signal for cell growth and proliferation.<br /> <br /> === Open Conformation ===<br /> In the <scene name='90/904315/Open_conformation/4'>open, active conformation</scene>, (REWRITE ABOUT RAS REGULATION)<br /> <br /> This transition is initiated by movement of the transition metal-binding site. The Cys 1032, His 1558, and His 1576 Residues become separated and zinc is not able to bond. In the active form, one protomer has its GRD and Sec14-PH domains oriented oppositely from the inactive form. The GRD rotates -130° and the Sec14-PH domain rotates -90° (TOWARDS WHAT?) Due to this rotation, Cys 1032 is now located too far away, approximately 30 Å, from His 1558 and His 1576 which results in the loss of the metal-binding site and no formation of the <scene name='90/904315/Open_conformation_triade/5'>triad</scene>. The lack of the transition metal-binding site allows the GRD to orient itself to associate with <scene name='90/904315/Ras_open_conformation/3'>Ras</scene>. This association positions the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> (TO DO WHAT?). When Neurofibromin is in the open, active conformation, Arg 1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:Domain Rotation.jpg|500 px|left|thumb|Figure 3: Rotation of the GRD and Sec14-PH domains from the closed conformation (7PGR) of neurofibromin to the open conformation (7PGT) of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> <br /> <br /> == Disease and Medical Relevance ==<br /> Currently over 1485 mutations of Neurofibromin have been identified that lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I.<ref name="Lupton">PMID: 34887559 </ref> Mutations to the NF1 gene that prevent the interaction of Neurofibromin with Ras, remove this check on Ras-dependent cell proliferation and uncontrolled cell growth can lead to tumors and a higher risk of cancer. [https://en.wikipedia.org/wiki/Neurofibromatosis_type_I Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called [https://en.wikipedia.org/wiki/Caf%C3%A9_au_lait_spot cafe-au-lait macules], clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is also involved in the differentiation of [https://en.wikipedia.org/wiki/Neural_crest neural crest-derived cells], [https://en.wikipedia.org/wiki/Mesenchymal_stem_cell mesenchymal cells], [https://en.wikipedia.org/wiki/Neural_stem_cell neural cells], [https://en.wikipedia.org/wiki/Melanocyte melanocytes], and [https://en.wikipedia.org/wiki/Osteocyte bone cells]. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 point mutations identified lead to a synthesis of truncated, non-functional protein. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases result from de novo mutations. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations in the NF1 gene have been found in sporadic cancers such as [https://en.wikipedia.org/wiki/Glioblastoma glioblastoma], [https://en.wikipedia.org/wiki/Neuroblastoma neuroblastoma], [https://en.wikipedia.org/wiki/Lung_cancer lung cancer], [https://en.wikipedia.org/wiki/Ovarian_cancer ovarian cancer], and [https://en.wikipedia.org/wiki/Breast_cancer breast cancer]. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Aldolase&diff=3539692 Aldolase 2022-04-01T00:51:18Z

<p>Sophie Mullinix: </p> <hr /> <div><StructureSection load='3mmt' size='340' side='right' caption='Fructose 1,6-bisphosphate aldolase tetramer complex with fructose 1,6-bisphosphate, [[3mmt]]|' scene=''><br /> =Aldolase class I=<br /> <br /> '''Fructose-6-phosphate aldolase''' catalyzes the cleavage of fructose-6-phosphate<ref>PMID:11120740</ref>.<br /><br /> '''Deoxyribose-phosphate aldolase''' cconverts 2-deoxy-D-ribose-5-phosphate into glyceraldehyde 3-phosphate and acetaldehyde<ref>PMID:25229427</ref>.<br /><br /> '''Dihydroneopterin aldolase''' catalyzes the conversion of 7,8-dihydropterin to 6-hydroxymethyl-7,8-dihydropterin. It is part of the folate synthesis <ref>PMID:15107504</ref>.<br /><br /> '''Sialic acid aldolase''' catalyzes the condensation of pyruvate and N-acetylmannosamine<ref>PMID:11674166</ref>.<br /><br /> '''Oxoadipate aldolase''' catalyzes the last step of the bacterial protocatechuate 4,5-cleavage pathway<ref>PMID:20843800</ref>.<br /><br /> '''Oxovalerate aldolase''' catalyzes the conversion of 4-hydroxy-2-oxopentanoate to acetaldehyde and pyruvate<ref>PMID:8419288</ref>.<br /><br /> '''2-keto-deoxydephosphogluconate aldolase''' catalyzes the cleavage of 2-keto-deoxydephosphogluconate<ref>PMID:12876349</ref>.<br /><br /> =Aldolase class II. Metal-dependent aldolase=<br /> <br /> '''Fructose-1,6-bisphosphate aldolase''' catalyzes the conversion of fructose-1,6-bisphosphatealdol to dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (G3P) <ref>PMID:10712619</ref>.<br /><br /> '''Tagatose-1,6-bisphosphate aldolase''' catalyzes the aldol condensation of DHAP with G3P to produce tagatose 1,6-bisphosphate<ref>PMID:11940603</ref>.<br /><br /> '''Fuculose-1-phosphate aldolase''' catalyzes the cleavage of fuculose-1-phosphate to dihydroxyacetone phosphate (DHAP) and lactaldehyde<ref>PMID:10821675</ref>.<br /><br /> '''HpcH/HpaI aldolase''' catalyzes the conversion of 4-hydroxy-2-oxo-heptane-1,7-dioate into pyruvate and succinate. It is part of the aromatic compounds degradation<ref>PMID:17881002</ref>.<br /><br /> '''Oxoglutarate aldolase''' catalyzes the cleavage of 4-hydroxy-2-oxoglutarate into pyruvate and glyoxylate. It belongs to the hydroxyproline degradation pathway<ref>PMID:21998747</ref>.<br /><br /> '''Threonine aldolase''' catalyzes the cleavage of threonine into glycine and acetaldehyde. It is part of the glycine, serine and threonine metabolism pathway<ref>PMID:13449064</ref>.<br /><br /> <br /> = Fructose Bisphosphate Aldolase =<br /> ==Introduction and Structure==<br /> '''Fructose bisphosphate aldolase''' is an enzyme in glycolysis and gluconeogenesis. Glycolyis is responsible for the conversion of glucose into two three-carbon pyruvate molecules without the need for oxygen. The process generates two net ATP. The overall reaction is:<br /> <br /> Glucose + 2 NAD+ + 2 ADP + 2 Pi --> 2 pyruvate (3-carbon product) + 2 NADH + 2 ATP + 2 H<sub>2</sub>0 + 4 H+<br /> <br /> Gluconeogenesis is responsible for maintaining the appropriate levels of blood glucose in animals by generating glucose from non-carbohydrate precursors. Gluconeogenesis can make glucose from lactate, pyruvate, citric acid cycle intermediates and from most amino acids (the exceptions being leucine and lysine). The common intermediate for all of the precursors on their way to becoming glucose must be oxaloacetate.<br /> <br /> The aldolase catalyzes the reversible cleavage of fructose-1,6-bisphosphate into dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GAP). Different isozymes of aldolase can also catalyze the cleavage of fructose 1-phosphate to diydroxyacetone and glyceraldehyde (GA). Different isozymes exhibit preferences for either or both of the substrates, depending on the role of the aldolase (i.e. gluconeogenesis versus glycolysis).<ref name="book">Voet, D, Voet, J, & Pratt, C. (2008). Fundamentals of biochemistry, third edition. Hoboken, NJ: Wiley & Sons, Inc.</ref> See also [[Enzimas: complejo enzima-sustrato]] (in Spanish) and [[Glycolysis Enzymes]].<br /> <br /> <br /> <br /> While it can exist as a monomer, it normally exists as a <scene name='Austin_Drake_Sandbox/Tetramer/3'>homotetramer</scene>. The enzyme is an a/B protein with a TIM beta/alpha beta fold. The fold designation is based upon the nine alpha helices and eight parallel beta sheets in a closed barrel of each monomeric subunit. It is part of the aldolase superfamily and the class I aldolases.<ref>Protein: fructose-1,6-bisphosphate aldolase from human (homo sapiens), muscle isozyme. (2009). Retrieved from http://scop.mrc-lmb.cam.ac.uk</ref> <scene name='Austin_Drake_Sandbox/Different_colors/3'>α helices and β sheets</scene> can be seen in their specific regions mostly concentric to the active site, represented by the blue and red residues.<br /> <br /> Although some form of fructose bisphosphate aldolase is present in nearly all living things, certain isoforms carry a large degree of conservation. The enzyme from rabbit muscle has nearly the tertiary and primary structure as the enzyme in human muscle. As a result, implications from rabbit muscle aldolase also reveal a great deal about the human forms of the enzyme. <ref name="review">Gefflaut, T., B. Casimir, J. Perie, and M. Willson. "Class I Aldolases: Substrate Specificity, Mechanism, Inhibitors and Structural Aspects." Prog. Biophys. molec. Biol.. 63. (1995): 301-340.</ref><br /> <br /> ==Binding and Catalysis==<br /> <br /> As an enzyme, the aldolase must not only encourage and favor the hydrolysis of fructose 1,6-bisphosphate, but also bind the substrate so as to hold it in the active site. The main-chain nitrogens of Ser271 and Gly272 hold the 1-phosphate group while the Lys41, Arg42 and Arg303 residues hold the 6-phosphate group. The five proposed binding residues are in close proximity to the catalytic Lys229, implicating them as participants in the binding process.<ref>PMID:10048322</ref> The <scene name='Austin_Drake_Sandbox/Tyr363/1'>C-terminus</scene>, which sits just outside of the barrel and catalytic site, of the enzyme also appears to contribute to the catalytic process of the aldolase. Mutations or suppression of the final tyrosine residue (Tyr363) causes a notable drop in the activity of the enzyme. Two cysteine residues have also been implicated in the catalytic process. Though they do not appear to be necessary for catalysis, modification of them does result in a decrease in catalytic activity. The two Cys residues are far from the active site, but do impact the movement of the C-terminus of the enzyme, which further implicates the terminus as participatory in the catalysis.<br /> <br /> The reaction is an aldol cleavage, or otherwise termed, retro aldo condensation. Catalysis occurs first when the nucleophilic ε-amine group of Lys229 attacks the carbonyl carbon of the substrate (FBP) in its open-ring state, pushing an electron pair to the oxygen of the carbonyl. The oxygen is protonated and leaves as water as a protonated <scene name='Austin_Drake_Sandbox/Schiff_base/2'>Schiff base</scene> is produced (an imine resulting from a ketone and amine) with the open-ring form of FBP, accompanied by electrostatic stabilization from <scene name='Austin_Drake_Sandbox/Catalytic_site_w_water/5'>Asp33</scene> Aldol cleavage between C3 and C4 produces GAP and an enamine precursor to DHAP.<ref name="book" /> The cleavage is facilitated by the positive charge from the Schiff base. The subsequent electron movement, which alleviates the positive charge, also breaks the C3-C4 bond.<ref name="review" /> Tautomerization, protonation and the hydrolysis of the Schiff base produce the final product of DHAP and regenerate the enzyme. The catalysis is driven by the more favorable stability of the protonated Schiff base compared to the enolate that would appear in basic catalysis pathways.<ref name="book" /> <br /> <br /> [[Image:Aldolase1.jpg|border|300px]]<br /> <br /> ==Kinetics==<br /> <br /> Isotopic labelling has revealed the rate-determining step for the reaction. Either the carbon-carbon bond cleavage or the release of glyceraldehyde-3-phosphate comprise the slow step of the catalysis reaction; however, studies do indicate that the GAP release is likely the slowest step.<ref name="review" /><br /> <br /> It has been shown that aldolase is inhibited allosterically by oxidized glutathione, which is an oxidizing species biologically present. The glutathione oxidizes a thiol 25 angstroms from the catalytic site, which subsequently causes a drop in catalytic activity. In addition, the enzyme shows no positive cooperativity, despite being an oligomer. In fact, kinetics data actually show that the enzyme exhibits negative cooperativity. Thus the catalysis is highly compartmentalized within each subunit and binding causes little distal change of the enzymes structure.<ref name="kinetics">Sygusch, J., and Beaudry, D. "Allosteric communication in mammalian muscle aldolase." Biochem. J.. 327. (1997): 717-720.</ref><br /> <br /> ==Regulation==<br /> <br /> The regulation of fructose 1,6-bisphosphate aldolase is not well understood, but the understanding is ever-increasing. As it is currently observed, aldolase C appears to be regulated mainly by the gene expression--the concentration of mRNA in the cytoplasm.<ref>Paolella, G, Buono, P, Mancini, F P, Izzo, P, and Salvatore, F. "Structure and expression of mouse aldolase genes." Eur. J. Biochem.. 156. (1986): 229-235.</ref> It is also known that adenosine 3',5'-cyclicmonophosphate (cAMP) affects the expression of the gene. cAMP concentration has been positively correlated with aldolase C expression. It is believed that cAMP acts upon a section of the promotor region, distal element D, causing the transcriptional promoter, NGFI-B, to bind. Once bound, the promoter activates the transcription of the gene coding for fructose bisphosphate aldolase.<ref>Buono, P, Cassano, S, Alfieri, A, Mancini, A, and Salvatore, F. "Human aldolase C gene expression is regulated by adenosine 30,50-cyclic monophosphate (cAMP) in PC12 cells." Gene. 291. (2002): 115-121.</ref> Given the inhibitory effects of an oxidant in the presence of aldolase, it is possible that this could be a mechanism of regulation of the enzyme. The deactivation that accompanies the oxidation of the surface thiol of Cys72 could be used intracellularly to slow the catalysis of the enzyme and regulate glycolysis.<ref name="kinetics" /><br /> <br /> =3D structures of aldolase=<br /> [[Aldolase 3D structures]]<br /> <br /> </StructureSection><br /> <br /> =Additional Resources=<br /> For additional information, see: [[Carbohydrate Metabolism]]<br /> <br /><br /> <br /> =References=<br /> <references/><br /> <br /> [[Category:Topic Page]]</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3536836 Sandbox Reserved 1710 2022-03-29T19:31:34Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation' scene='90/904315/Closed_spinning/2'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin.jpg|340 px|right|thumb|Surface Rendering of Neurofibromin in its Open and Closed Conformation]]<br /> Neurofibromin is a protein that is coded for by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 Gene] which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 by cryo-electron microscopy revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin is associated with diseases such as Plexiform Neurofibromas.<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/4'>homodimer</scene> made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.<br /> <br /> === Closed Conformation ===<br /> The first conformation of Neurofibromin is known as the <scene name='90/904315/Closed/2'>Closed Conformation</scene>, which is representative of an inactive Neurofibromin protein. In the closed conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive due to a <scene name='90/904315/Catalytic_triade/2'>triade</scene> consisting of residues Cysteine 1032, Histidine 1558, and Histidine 1576 that form a transition metal-binding site with zinc. The close proximity of the C1032, H1558, and H1576 residues that form the <scene name='90/904316/Closed_triade/3'>triade in closed conformation</scene> keep the GRD domain packed tightly on top of the Neurofibromin core. This tight compaction leads to steric inhibition when Neurofibromin tries to perform its function and associate with Ras. The association between Ras and Neurofibromin is supposed to occur via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> located at Residue 1276. However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, when Neurofibromin is in the closed conformation, there is no association with Ras and cell growth and proliferation is able to occur.<br /> <br /> === Open Conformation ===<br /> The other conformation that characterizes Neurofibromin is the <scene name='90/904315/Open_conformation/3'>Open Conformation</scene>. In the open conformation of Neurofibromin, the protein is considered active and is participating in its function of Ras regulation. This occurs because the transition metal-binding site with zinc no longer is able to form due to an increase in distance between the C1032, H1558 and H1576 residues that form the <scene name='90/904315/Open_conformation_triade/4'>Open Triade</scene>. One protomer in Neurofibromin has its GRD and Sec14-PH domains oriented in way that is almost reversed in position compared to the closed conformation. The GRD rotates -130° and the Sec14-PH domain rotates -90° in the transition between the closed and the open conformation. Due to this rotation, C1032 is now located too far away, approximately 30 Angstroms, from H1558 and H1576 which results in the loss of the metal-binding site. The lack of the transition metal-binding site allows the GRD to orient itself in such a way that it can associate with <scene name='90/904315/Ras_open_conformation/2'>Ras in the Open Conformation</scene>. The reason that Neurofibromin is only able to associate with Ras in the open conformation is due to one critical residue, the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> located at position 1276 in Neurofibromin. When Neurofibromin is in the open conformation, R1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:GRDandSec14PHRotation.jpg|340 px|left|thumb|Rotation of the GRD and Sec14-PH domains from the closed conformation of neurofibromin to the open conformation of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Function ==<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an Arginine finger (R1276) present in the GRD domain of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its Guanine triphosphatase-activating protein (GAP) activity; therefore, when there are mutations to the NF1 gene that prevent the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer.<ref name="Ratner">PMID:25877329</ref> [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called cafe-au-lait macules <ref name="Ratner">PMID:25877329</ref>, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is an essential protein and is involved mainly in the differentiation of neural crest-derived cells, mesenchymal cells, neural cells, melanocytes, and bone cells. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 mutations identified lead to a synthesis of truncated, non-functional protein and are a result of point mutations. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases de novo ones. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations of the gene NF1 can lead to major structural and functional changes that are dangerous for the patient. NF1 mutation(s) can result in the complete loss of function and the inability to interact with the Ras protein. If interaction with Ras cannot occur, no conversion of GTP to GDP occurs and, therefore, no inactivation of Ras. Consequently, there is nothing limiting Ras from promoting cell growth. Uncontrolled cell growth leads to tumors and puts patients at a much higher risk for cancer. Mutations in the NF1 gene have been found in sporadic cancers such as glioblastoma, neuroblastoma, lung cancer, ovarian cancer, and breast cancer. Additionally, NF1 is one of the top ten genes that are most mutated in tumors of the lung, breast, ovary, pancreas, and prostate. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors. It is possible that the order of mutations affects the grade of a tumor (for certain types of cells) and thus explains why NF1 patients are not predisposed to certain types of sporadic tumors.<ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3536818 Sandbox Reserved 1710 2022-03-29T19:14:19Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation' scene='90/904315/Closed_spinning/2'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin.jpg|340 px|right|thumb|Surface Rendering of Neurofibromin in its Open and Closed Conformation]]<br /> Neurofibromin is a protein that is coded for by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 Gene] which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 by cryo-electron microscopy revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin is associated with diseases such as Plexiform Neurofibromas.<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/4'>homodimer</scene> made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.<br /> <br /> === Closed Conformation ===<br /> The first conformation of Neurofibromin is known as the <scene name='90/904315/Closed/2'>Closed Conformation</scene>, which is representative of an inactive Neurofibromin protein. In the closed conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive due to a <scene name='90/904315/Catalytic_triade/2'>triade</scene> consisting of residues Cysteine 1032, Histidine 1558, and Histidine 1576 that form a transition metal-binding site with zinc. The close proximity of the C1032, H1558, and H1576 residues that form the <scene name='90/904316/Closed_triade/3'>triade in closed conformation</scene> keep the GRD domain packed tightly on top of the Neurofibromin core. This tight compaction leads to steric inhibition when Neurofibromin tries to perform its function and associate with Ras. The association between Ras and Neurofibromin is supposed to occur via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> located at Residue 1276. However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, when Neurofibromin is in the closed conformation, there is no association with Ras and cell growth and proliferation is able to occur.<br /> <br /> === Open Conformation ===<br /> The other conformation that characterizes Neurofibromin is the <scene name='90/904315/Open_conformation/3'>Open Conformation</scene>. In the open conformation of Neurofibromin, the protein is considered active and is participating in its function of Ras regulation. This occurs because the transition metal-binding site with zinc no longer is able to form due to an increase in distance between the C1032, H1558 and H1576 residues that form the <scene name='90/904315/Open_conformation_triade/4'>Open Triade</scene>. One protomer in Neurofibromin has its GRD and Sec14-PH domains oriented in way that is almost reversed in position compared to the closed conformation. The GRD rotates -130° and the Sec14-PH domain rotates -90° in the transition between the closed and the open conformation. Due to this rotation, C1032 is now located too far away, approximately 30 Angstroms, from H1558 and H1576 which results in the loss of the metal-binding site. The lack of the transition metal-binding site allows the GRD to orient itself in such a way that it can associate with <scene name='90/904315/Ras_open_conformation/2'>Ras in the Open Conformation</scene>. The reason that Neurofibromin is only able to associate with Ras in the open conformation is due to one critical residue, the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> located at position 1276 in Neurofibromin. When Neurofibromin is in the open conformation, R1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:GRDandSec14PHRotation.jpg|340 px|left|thumb|Rotation of the GRD and Sec14-PH domains from the closed conformation of neurofibromin to the open conformation of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Function ==<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an Arginine finger (R1276) present in the GRD domain of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its Guanine triphosphatase-activating protein (GAP) activity; therefore, when there are mutations to the NF1 gene that prevent the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer.<ref name="Ratner">PMID:25877329</ref> [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called cafe-au-lait macules <ref name="Ratner">PMID:25877329</ref>, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is an essential protein and is involved mainly in the differentiation of neural crest-derived cells, mesenchymal cells, neural cells, melanocytes, and bone cells. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 mutations identified lead to a synthesis of truncated, non-functional protein and are a result of point mutations. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases de novo ones. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations of the gene NF1 can lead to major structural and functional changes that are dangerous for the patient. Here is the process of how a mutation could lead to life-threatening illnesses or conditions: If there is a mutation in the NF1 gene, this results in a loss of function of the Neurofibromin completely and/or the inability to interact with the Ras protein. If it cannot interact with Ras, there is no GTP to GDP, inactivating the Ras, meaning there is nothing that is limiting the Ras from promoting cell growth. Uncontrolled cell growth leads to tumors and patients are at a much higher risk for cancer. Mutations in NF1 have been found in sporadic cancers that are not even NF1 associated, which includes glioblastoma, neuroblastoma, lung cancer, ovarian cancer, and breast cancer. Additionally, NF1 is in the top ten genes that are most mutated in tumors of the lung, breast, ovary, pancreas, and prostate. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors. It is possible that the order of mutations affects the grade of a tumor for certain types of cells and thus explains why NF1 patients are not predisposed to certain types of sporadic tumors. <ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3536809 Sandbox Reserved 1710 2022-03-29T19:08:54Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation' scene='90/904315/Closed_spinning/2'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin.jpg|340 px|right|thumb|Surface Rendering of Neurofibromin in its Open and Closed Conformation]]<br /> Neurofibromin is a protein that is coded for by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 Gene] which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 by cryo-electron microscopy revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin is associated with diseases such as Plexiform Neurofibromas.<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/4'>homodimer</scene> made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.<br /> <br /> === Closed Conformation ===<br /> The first conformation of Neurofibromin is known as the <scene name='90/904315/Closed/2'>Closed Conformation</scene>, which is representative of an inactive Neurofibromin protein. In the closed conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive due to a <scene name='90/904315/Catalytic_triade/2'>triade</scene> consisting of residues Cysteine 1032, Histidine 1558, and Histidine 1576 that form a transition metal-binding site with zinc. The close proximity of the C1032, H1558, and H1576 residues that form the <scene name='90/904316/Closed_triade/1'>triade in the closed conformation</scene> keep the GRD domain packed tightly on top of the Neurofibromin core. This tight compaction leads to steric inhibition when Neurofibromin tries to perform its function and associate with Ras. The association between Ras and Neurofibromin is supposed to occur via an <scene name='90/904316/Arg_finger/2'>Arginine finger</scene> located at Residue 1276. However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, when Neurofibromin is in the closed conformation, there is no association with Ras and cell growth and proliferation is able to occur.<br /> <br /> === Open Conformation ===<br /> The other conformation that characterizes Neurofibromin is the <scene name='90/904315/Open_conformation/3'>Open Conformation</scene>. In the open conformation of Neurofibromin, the protein is considered active and is participating in its function of Ras regulation. This occurs because the transition metal-binding site with zinc no longer is able to form due to an increase in distance between the C1032, H1558 and H1576 residues that form the <scene name='90/904315/Open_conformation_triade/4'>Open Triade</scene>. One protomer in Neurofibromin has its GRD and Sec14-PH domains oriented in way that is almost reversed in position compared to the closed conformation. Due to this rotation, C1032 is now located too far away, approximately 30 Angstroms, from H1558 and H1576 which results in the loss of the metal-binding site. The lack of the transition metal-binding site allows the GRD to orient itself in such a way that it can associate with <scene name='90/904315/Ras_open_conformation/2'>Ras in the Open Conformation</scene>. The reason that Neurofibromin is only able to associate with Ras in the open conformation is due to one critical residue, the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> located at position 1276 in Neurofibromin. When Neurofibromin is in the open conformation, R1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:GRDandSec14PHRotation.jpg|340 px|left|thumb|Rotation of the GRD and Sec14-PH domains from the closed conformation of neurofibromin to the open conformation of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Function ==<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an Arginine finger (R1276) present in the GRD domain of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its Guanine triphosphatase-activating protein (GAP) activity; therefore, when there are mutations to the NF1 gene that prevent the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer.<ref name="Ratner">PMID:25877329</ref> [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called cafe-au-lait macules <ref name="Ratner">PMID:25877329</ref>, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is an essential protein and is involved mainly in the differentiation of neural crest-derived cells, mesenchymal cells, neural cells, melanocytes, and bone cells. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 mutations identified lead to a synthesis of truncated, non-functional protein and are a result of point mutations. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases de novo ones. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations of the gene NF1 can lead to major structural and functional changes that are dangerous for the patient. Here is the process of how a mutation could lead to life-threatening illnesses or conditions: If there is a mutation in the NF1 gene, this results in a loss of function of the Neurofibromin completely and/or the inability to interact with the Ras protein. If it cannot interact with Ras, there is no GTP to GDP, inactivating the Ras, meaning there is nothing that is limiting the Ras from promoting cell growth. Uncontrolled cell growth leads to tumors and patients are at a much higher risk for cancer. Mutations in NF1 have been found in sporadic cancers that are not even NF1 associated, which includes glioblastoma, neuroblastoma, lung cancer, ovarian cancer, and breast cancer. Additionally, NF1 is in the top ten genes that are most mutated in tumors of the lung, breast, ovary, pancreas, and prostate. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors. It is possible that the order of mutations affects the grade of a tumor for certain types of cells and thus explains why NF1 patients are not predisposed to certain types of sporadic tumors. <ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1711&diff=3536807 Sandbox Reserved 1711 2022-03-29T19:08:03Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> Neurofibromin is a <scene name='90/905640/Homodimer/1'>homodimer</scene> with two identical chains (depicted as lime and cyan).<br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> In the overall <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene> (and inactive) conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive. The closed conformation has both of the protomers/chains in the closed positions, whereas the open conformation has one closed and one open protomer. You can see that in the closed conformation, Ras binding by the GRD domain is sterically hindered and there is no room for association with the Ras protein. <br /> The closed conformation has the GRD and Sec14-PH domains oriented in a way that the amino acids C1032, H1558, and H1576 are in close proximity to each other to form a transition metal-binding site with zinc. The fourth coordination partner in this is water. <br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene> <br /> <br /> === Domains ===<br /> The <scene name='90/904316/Grd_domains/2'>GRD</scene> of Neurofibromin, specifically the arginine finger (R1276), binds to the Ras + GTP complex.<br /> === Key Players ===<br /> An <scene name='90/904316/Arg_finger/2'>Arginine finger</scene>(R1276) <scene name='90/904316/Arg_finger/1'>R1276</scene> present in the GRD is critical for Ras binding and is only accessible when the GRD and Sec14-PH domains are rotated in such a way that there is no steric hindrance from the surrounding dimer chains. The Closed conformation is stabilized by a <scene name='90/904316/Closed_triade/1'>triade</scene> of residues that are coordinated with transition metal-binding sites with zinc. Here, the GRD and Sec14-PH domains are oriented in a way that the H1558 and H1576 are able to interact with C1032 and form a transition binding-site with zinc. This binding site stabilizes the closed conformation and prevents Ras from associating with the GRD based on the location of the GRD in relation to the rest of the protein. <br /> == Function ==<br /> The GRD arginine finger (R1276) is crucial in Ras binding. When Neurofibromin is in the open conformation, the Arginine finger is able to bind with Ras because the Arginine is not inhibited as it would be in the closed conformation, where R1276 is facing the core and inaccessible due to the rotation of the two domains. This open conformation allows neurofibromin to associate with Ras via R1276 binding, which then hydrolyzes the Ras from active GTP to inactive GDP, showing why R1276 is crucial to neurofibromin function. In the open conformation, on the other hand, the arginine finger is able to interact with Ras and hydrolyze it which effectively turns it off. <br /> === Ras Control ===<br /> Ras is still promoting cell proliferation in this closed conformation because Neurofibromin is unable to hydrolyze Ras and inactivate it. In this open conformation, the Ras is not sterically hindered and the Arginine finger is accessible for Ras binding, thus allowing Neurofibromin to down-regulate Ras.<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3536796 Sandbox Reserved 1710 2022-03-29T19:02:03Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation' scene='90/904315/Closed_spinning/2'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin.jpg|340 px|right|thumb|Surface Rendering of Neurofibromin in its Open and Closed Conformation]]<br /> Neurofibromin is a protein that is coded for by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 Gene] which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 by cryo-electron microscopy revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin is associated with diseases such as Plexiform Neurofibromas.<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/4'>homodimer</scene> made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.<br /> <br /> === Closed Conformation ===<br /> The first conformation of Neurofibromin is known as the <scene name='90/904315/Closed/2'>Closed Conformation</scene>, which is representative of an inactive Neurofibromin protein. In the closed conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive due to a <scene name='90/904315/Catalytic_triade/2'>triade</scene> consisting of residues Cysteine 1032, Histidine 1558, and Histidine 1576 that form a transition metal-binding site with zinc. The close proximity of the C1032, H1558, and H1576 residues that form the <scene name='90/904316/Closed_triade/1'>triade in the closed conformation</scene> keep the GRD domain packed tightly on top of the Neurofibromin core. This tight compaction leads to steric inhibition when Neurofibromin tries to perform its function and associate with Ras. The association between Ras and Neurofibromin is supposed to occur via an <scene name='90/904316/Arg_finger/1'>Arginine Finger</scene> located at Residue 1276. However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, when Neurofibromin is in the closed conformation, there is no association with Ras and cell growth and proliferation is able to occur.<br /> <br /> === Open Conformation ===<br /> The other conformation that characterizes Neurofibromin is the <scene name='90/904315/Open_conformation/3'>Open Conformation</scene>. In the open conformation of Neurofibromin, the protein is considered active and is participating in its function of Ras regulation. This occurs because the transition metal-binding site with zinc no longer is able to form due to an increase in distance between the C1032, H1558 and H1576 residues that form the <scene name='90/904315/Open_conformation_triade/4'>Open Triade</scene>. One protomer in Neurofibromin has its GRD and Sec14-PH domains oriented in way that is almost reversed in position compared to the closed conformation. Due to this rotation, C1032 is now located too far away, approximately 30 Angstroms, from H1558 and H1576 which results in the loss of the metal-binding site. The lack of the transition metal-binding site allows the GRD to orient itself in such a way that it can associate with <scene name='90/904315/Ras_open_conformation/2'>Ras in the Open Conformation</scene>. The reason that Neurofibromin is only able to associate with Ras in the open conformation is due to one critical residue, the <scene name='90/904315/Open_conformation_arginine_fin/2'>Arginine Finger</scene> located at position 1276 in Neurofibromin. When Neurofibromin is in the open conformation, R1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/2'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:GRDandSec14PHRotation.jpg|340 px|left|thumb|Rotation of the GRD and Sec14-PH domains from the closed conformation of neurofibromin to the open conformation of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Function ==<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an Arginine finger (R1276) present in the GRD domain of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its Guanine triphosphatase-activating protein (GAP) activity; therefore, when there are mutations to the NF1 gene that prevent the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer.<ref name="Ratner">PMID:25877329</ref> [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called cafe-au-lait macules <ref name="Ratner">PMID:25877329</ref>, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is an essential protein and is involved mainly in the differentiation of neural crest-derived cells, mesenchymal cells, neural cells, melanocytes, and bone cells. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 mutations identified lead to a synthesis of truncated, non-functional protein and are a result of point mutations. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases de novo ones. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations of the gene NF1 can lead to major structural and functional changes that are dangerous for the patient. Here is the process of how a mutation could lead to life-threatening illnesses or conditions: If there is a mutation in the NF1 gene, this results in a loss of function of the Neurofibromin completely and/or the inability to interact with the Ras protein. If it cannot interact with Ras, there is no GTP to GDP, inactivating the Ras, meaning there is nothing that is limiting the Ras from promoting cell growth. Uncontrolled cell growth leads to tumors and patients are at a much higher risk for cancer. Mutations in NF1 have been found in sporadic cancers that are not even NF1 associated, which includes glioblastoma, neuroblastoma, lung cancer, ovarian cancer, and breast cancer. Additionally, NF1 is in the top ten genes that are most mutated in tumors of the lung, breast, ovary, pancreas, and prostate. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors. It is possible that the order of mutations affects the grade of a tumor for certain types of cells and thus explains why NF1 patients are not predisposed to certain types of sporadic tumors. <ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1711&diff=3536791 Sandbox Reserved 1711 2022-03-29T19:00:27Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> Neurofibromin is a <scene name='90/905640/Homodimer/1'>homodimer</scene> with two identical chains (depicted as lime and cyan).<br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> In the overall <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene> (and inactive) conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive. The closed conformation has both of the protomers/chains in the closed positions, whereas the open conformation has one closed and one open protomer. You can see that in the closed conformation, Ras binding by the GRD domain is sterically hindered and there is no room for association with the Ras protein. <br /> The closed conformation has the GRD and Sec14-PH domains oriented in a way that the amino acids C1032, H1558, and H1576 are in close proximity to each other to form a transition metal-binding site with zinc. The fourth coordination partner in this is water. <br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene> <br /> <br /> === Domains ===<br /> The <scene name='90/904316/Grd_domains/2'>GRD</scene> of Neurofibromin, specifically the arginine finger (R1276), binds to the Ras + GTP complex.<br /> === Key Players ===<br /> An <scene name='90/905640/Arg_finger/1'>R1276</scene> (R1276) <scene name='90/904316/Arg_finger/1'>R1276</scene> present in the GRD is critical for Ras binding and is only accessible when the GRD and Sec14-PH domains are rotated in such a way that there is no steric hindrance from the surrounding dimer chains. The Closed conformation is stabilized by a <scene name='90/904316/Closed_triade/1'>triade</scene> of residues that are coordinated with transition metal-binding sites with zinc. Here, the GRD and Sec14-PH domains are oriented in a way that the H1558 and H1576 are able to interact with C1032 and form a transition binding-site with zinc. This binding site stabilizes the closed conformation and prevents Ras from associating with the GRD based on the location of the GRD in relation to the rest of the protein. <br /> == Function ==<br /> The GRD arginine finger (R1276) is crucial in Ras binding. When Neurofibromin is in the open conformation, the Arginine finger is able to bind with Ras because the Arginine is not inhibited as it would be in the closed conformation, where R1276 is facing the core and inaccessible due to the rotation of the two domains. This open conformation allows neurofibromin to associate with Ras via R1276 binding, which then hydrolyzes the Ras from active GTP to inactive GDP, showing why R1276 is crucial to neurofibromin function. In the open conformation, on the other hand, the arginine finger is able to interact with Ras and hydrolyze it which effectively turns it off. <br /> === Ras Control ===<br /> Ras is still promoting cell proliferation in this closed conformation because Neurofibromin is unable to hydrolyze Ras and inactivate it. In this open conformation, the Ras is not sterically hindered and the Arginine finger is accessible for Ras binding, thus allowing Neurofibromin to down-regulate Ras.<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3536768 Sandbox Reserved 1710 2022-03-29T18:47:41Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation' scene='90/904315/Closed_spinning/2'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin.jpg|340 px|right|thumb|Surface Rendering of Neurofibromin in its Open and Closed Conformation]]<br /> Neurofibromin is a protein that is coded for by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 Gene] which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 by cryo-electron microscopy revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin is associated with diseases such as Plexiform Neurofibromas.<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/4'>homodimer</scene> made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and closed conformations, the <scene name='90/904316/Grd_domains/1'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/3'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.<br /> <br /> === Closed Conformation ===<br /> The first conformation of Neurofibromin is known as the <scene name='90/904315/Closed/2'>Closed Conformation</scene>, which is representative of an inactive Neurofibromin protein. In the closed conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive due to a <scene name='90/904315/Catalytic_triade/2'>triade</scene> consisting of residues Cysteine 1032, Histidine 1558, and Histidine 1576 that form a transition metal-binding site with zinc. The close proximity of the C1032, H1558, and H1576 residues that form the <scene name='90/904316/Closed_triade/2'>triade in the closed conformation</scene> keep the GRD domain packed tightly on top of the Neurofibromin core. This tight compaction leads to steric inhibition when Neurofibromin tries to perform its function and associate with Ras. The association between Ras and Neurofibromin is supposed to occur via an <scene name='90/904316/Arg_finger/2'>Arginine Finger</scene> located at Residue 1276. However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, when Neurofibromin is in the closed conformation, there is no association with Ras and cell growth and proliferation is able to occur.<br /> <br /> === Open Conformation ===<br /> The other conformation that characterizes Neurofibromin is the <scene name='90/904315/Open_conformation/3'>Open Conformation</scene>. In the open conformation of Neurofibromin, the protein is considered active and is participating in its function of Ras regulation. This occurs because the transition metal-binding site with zinc no longer is able to form due to an increase in distance between the C1032, H1558 and H1576 residues that form the <scene name='90/904315/Open_conformation_triade/3'>Open Triade</scene>. One protomer in Neurofibromin has its GRD and Sec14-PH domains oriented in way that is almost reversed in position compared to the closed conformation. Due to this rotation, C1032 is now located too far away, approximately 30 Angstroms, from H1558 and H1576 which results in the loss of the metal-binding site. The lack of the transition metal-binding site allows the GRD to orient itself in such a way that it can associate with <scene name='90/904315/Ras_open_conformation/1'>Ras in the Open Conformation</scene>. The reason that Neurofibromin is only able to associate with Ras in the open conformation is due to one critical residue, the <scene name='90/904315/Open_conformation_arginine_fin/1'>Arginine Finger</scene> located at position 1276 in Neurofibromin. When Neurofibromin is in the open conformation, R1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/1'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:GRDandSec14PHRotation.jpg|340 px|left|thumb|Rotation of the GRD and Sec14-PH domains from the closed conformation of neurofibromin to the open conformation of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Function ==<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an Arginine finger (R1276) present in the GRD domain of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its Guanine triphosphatase-activating protein (GAP) activity; therefore, when there are mutations to the NF1 gene that prevent the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer.<ref name="Ratner">PMID:25877329</ref> [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called cafe-au-lait macules <ref name="Ratner">PMID:25877329</ref>, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is an essential protein and is involved mainly in the differentiation of neural crest-derived cells, mesenchymal cells, neural cells, melanocytes, and bone cells. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 mutations identified lead to a synthesis of truncated, non-functional protein and are a result of point mutations. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases de novo ones. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations of the gene NF1 can lead to major structural and functional changes that are dangerous for the patient. Here is the process of how a mutation could lead to life-threatening illnesses or conditions: If there is a mutation in the NF1 gene, this results in a loss of function of the Neurofibromin completely and/or the inability to interact with the Ras protein. If it cannot interact with Ras, there is no GTP to GDP, inactivating the Ras, meaning there is nothing that is limiting the Ras from promoting cell growth. Uncontrolled cell growth leads to tumors and patients are at a much higher risk for cancer. Mutations in NF1 have been found in sporadic cancers that are not even NF1 associated, which includes glioblastoma, neuroblastoma, lung cancer, ovarian cancer, and breast cancer. Additionally, NF1 is in the top ten genes that are most mutated in tumors of the lung, breast, ovary, pancreas, and prostate. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors. It is possible that the order of mutations affects the grade of a tumor for certain types of cells and thus explains why NF1 patients are not predisposed to certain types of sporadic tumors. <ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1711&diff=3536765 Sandbox Reserved 1711 2022-03-29T18:44:14Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> Neurofibromin is a <scene name='90/905640/Homodimer/1'>homodimer</scene> with two identical chains (depicted as lime and cyan).<br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> In the overall <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene> (and inactive) conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive. The closed conformation has both of the protomers/chains in the closed positions, whereas the open conformation has one closed and one open protomer. You can see that in the closed conformation, Ras binding by the GRD domain is sterically hindered and there is no room for association with the Ras protein. <br /> The closed conformation has the GRD and Sec14-PH domains oriented in a way that the amino acids C1032, H1558, and H1576 are in close proximity to each other to form a transition metal-binding site with zinc. The fourth coordination partner in this is water. <br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene> <br /> <br /> === Domains ===<br /> The <scene name='90/904316/Grd_domains/1'>GRD domain</scene> of Neurofibromin, specifically the arginine finger (R1276), binds to the Ras + GTP complex.<br /> === Key Players ===<br /> An <scene name='90/905640/Arg_finger/1'>R1276</scene> (R1276) <scene name='90/904316/Arg_finger/1'>R1276</scene> present in the GRD is critical for Ras binding and is only accessible when the GRD and Sec14-PH domains are rotated in such a way that there is no steric hindrance from the surrounding dimer chains. The Closed conformation is stabilized by a <scene name='90/904316/Closed_triade/1'>triade</scene> of residues that are coordinated with transition metal-binding sites with zinc. Here, the GRD and Sec14-PH domains are oriented in a way that the H1558 and H1576 are able to interact with C1032 and form a transition binding-site with zinc. This binding site stabilizes the closed conformation and prevents Ras from associating with the GRD based on the location of the GRD in relation to the rest of the protein. <br /> == Function ==<br /> The GRD arginine finger (R1276) is crucial in Ras binding. When Neurofibromin is in the open conformation, the Arginine finger is able to bind with Ras because the Arginine is not inhibited as it would be in the closed conformation, where R1276 is facing the core and inaccessible due to the rotation of the two domains. This open conformation allows neurofibromin to associate with Ras via R1276 binding, which then hydrolyzes the Ras from active GTP to inactive GDP, showing why R1276 is crucial to neurofibromin function. In the open conformation, on the other hand, the arginine finger is able to interact with Ras and hydrolyze it which effectively turns it off. <br /> === Ras Control ===<br /> Ras is still promoting cell proliferation in this closed conformation because Neurofibromin is unable to hydrolyze Ras and inactivate it. In this open conformation, the Ras is not sterically hindered and the Arginine finger is accessible for Ras binding, thus allowing Neurofibromin to down-regulate Ras.<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3536718 Sandbox Reserved 1710 2022-03-29T17:01:53Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation' scene='90/904315/Closed_spinning/2'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin.jpg|340 px|right|thumb|Surface Rendering of Neurofibromin in its Open and Closed Conformation]]<br /> Neurofibromin is a protein that is coded for by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 Gene] which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 by cryo-electron microscopy revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin is associated with diseases such as Plexiform Neurofibromas.<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/3'>homodimer</scene> made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and closed conformations, the <scene name='90/905640/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/2'>Sec14-PH</scene> domain (observed here in the closed conformation). Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.<br /> <br /> === Closed Conformation ===<br /> The first conformation of Neurofibromin is known as the <scene name='90/904315/Closed/1'>Closed Conformation</scene>, which is representative of an inactive Neurofibromin protein. In the closed conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive due to a <scene name='90/904315/Catalytic_triade/1'>triade</scene> consisting of residues Cysteine 1032, Histidine 1558, and Histidine 1576 that form a transition metal-binding site with zinc. The close proximity of the C1032, H1558, and H1576 residues that form the <scene name='90/904316/Closed_triade/1'>triade in the closed conformation</scene> keep the GRD domain packed tightly on top of the Neurofibromin core. This tight compaction leads to steric inhibition when Neurofibromin tries to perform its function and associate with Ras. The association between Ras and Neurofibromin is supposed to occur via an <scene name='90/904316/Arg_finger/1'>Arginine Finger</scene> located at Residue 1276. However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, when Neurofibromin is in the closed conformation, there is no association with Ras and cell growth and proliferation is able to occur.<br /> <br /> === Open Conformation ===<br /> The other conformation that characterizes Neurofibromin is the <scene name='90/904315/Open_conformation/2'>Open Conformation</scene>. In the open conformation of Neurofibromin, the protein is considered active and is participating in its function of Ras regulation. This occurs because the transition metal-binding site with zinc no longer is able to form due to an increase in distance between the C1032, H1558 and H1576 residues that form the <scene name='90/904315/Open_conformation_triade/3'>Open Triade</scene>. One protomer in Neurofibromin has its GRD and Sec14-PH domains oriented in way that is almost reversed in position compared to the closed conformation. Due to this rotation, C1032 is now located too far away, approximately 30 Angstroms, from H1558 and H1576 which results in the loss of the metal-binding site. The lack of the transition metal-binding site allows the GRD to orient itself in such a way that it can associate with <scene name='90/904315/Ras_open_conformation/1'>Ras in the Open Conformation</scene>. The reason that Neurofibromin is only able to associate with Ras in the open conformation is due to one critical residue, the <scene name='90/904315/Open_conformation_arginine_fin/1'>Arginine Finger</scene> located at position 1276 in Neurofibromin. When Neurofibromin is in the open conformation, R1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/1'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:GRDandSec14PHRotation.jpg|340 px|left|thumb|Rotation of the GRD and Sec14-PH domains from the closed conformation of neurofibromin to the open conformation of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Function ==<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an Arginine finger (R1276) present in the GRD domain of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its Guanine triphosphatase-activating protein (GAP) activity; therefore, when there are mutations to the NF1 gene that prevent the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer.<ref name="Ratner">PMID:25877329</ref> [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called cafe-au-lait macules <ref name="Ratner">PMID:25877329</ref>, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is an essential protein and is involved mainly in the differentiation of neural crest-derived cells, mesenchymal cells, neural cells, melanocytes, and bone cells. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 mutations identified lead to a synthesis of truncated, non-functional protein and are a result of point mutations. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases de novo ones. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations of the gene NF1 can lead to major structural and functional changes that are dangerous for the patient. Here is the process of how a mutation could lead to life-threatening illnesses or conditions: If there is a mutation in the NF1 gene, this results in a loss of function of the Neurofibromin completely and/or the inability to interact with the Ras protein. If it cannot interact with Ras, there is no GTP to GDP, inactivating the Ras, meaning there is nothing that is limiting the Ras from promoting cell growth. Uncontrolled cell growth leads to tumors and patients are at a much higher risk for cancer. Mutations in NF1 have been found in sporadic cancers that are not even NF1 associated, which includes glioblastoma, neuroblastoma, lung cancer, ovarian cancer, and breast cancer. Additionally, NF1 is in the top ten genes that are most mutated in tumors of the lung, breast, ovary, pancreas, and prostate. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors. It is possible that the order of mutations affects the grade of a tumor for certain types of cells and thus explains why NF1 patients are not predisposed to certain types of sporadic tumors. <ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3536717 Sandbox Reserved 1710 2022-03-29T16:57:56Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation' scene='90/904315/Closed_spinning/2'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin.jpg|340 px|right|thumb|Surface Rendering of Neurofibromin in its Open and Closed Conformation]]<br /> Neurofibromin is a protein that is coded for by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 Gene] which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 by cryo-electron microscopy revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin is associated with diseases such as Plexiform Neurofibromas.<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/3'>homodimer</scene> made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and closed conformations, the <scene name='90/905640/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/2'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.<br /> <br /> === Closed Conformation ===<br /> The first conformation of Neurofibromin is known as the <scene name='90/904315/Closed/1'>Closed Conformation</scene>, which is representative of an inactive Neurofibromin protein. In the closed conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive due to a <scene name='90/904315/Catalytic_triade/1'>triade</scene> consisting of residues Cysteine 1032, Histidine 1558, and Histidine 1576 that form a transition metal-binding site with zinc. The close proximity of the C1032, H1558, and H1576 residues that form the <scene name='90/904316/Closed_triade/1'>triade in the closed conformation</scene> keep the GRD domain packed tightly on top of the Neurofibromin core. This tight compaction leads to steric inhibition when Neurofibromin tries to perform its function and associate with Ras. The association between Ras and Neurofibromin is supposed to occur via an <scene name='90/904316/Arg_finger/1'>Arginine Finger</scene> located at Residue 1276. However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, when Neurofibromin is in the closed conformation, there is no association with Ras and cell growth and proliferation is able to occur.<br /> <br /> === Open Conformation ===<br /> The other conformation that characterizes Neurofibromin is the <scene name='90/904315/Open_conformation/2'>Open Conformation</scene>. In the open conformation of Neurofibromin, the protein is considered active and is participating in its function of Ras regulation. This occurs because the transition metal-binding site with zinc no longer is able to form due to an increase in distance between the C1032, H1558 and H1576 residues that form the <scene name='90/904315/Open_conformation_triade/3'>Open Triade</scene>. One protomer in Neurofibromin has its GRD and Sec14-PH domains oriented in way that is almost reversed in position compared to the closed conformation. Due to this rotation, C1032 is now located too far away, approximately 30 Angstroms, from H1558 and H1576 which results in the loss of the metal-binding site. The lack of the transition metal-binding site allows the GRD to orient itself in such a way that it can associate with <scene name='90/904315/Ras_open_conformation/1'>Ras in the Open Conformation</scene>. The reason that Neurofibromin is only able to associate with Ras in the open conformation is due to one critical residue, the <scene name='90/904315/Open_conformation_arginine_fin/1'>Arginine Finger</scene> located at position 1276 in Neurofibromin. When Neurofibromin is in the open conformation, R1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/1'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:GRDandSec14PHRotation.jpg|340 px|left|thumb|Rotation of the GRD and Sec14-PH domains from the closed conformation of neurofibromin to the open conformation of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Function ==<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an Arginine finger (R1276) present in the GRD domain of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its Guanine triphosphatase-activating protein (GAP) activity; therefore, when there are mutations to the NF1 gene that prevent the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer.<ref name="Ratner">PMID:25877329</ref> [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called cafe-au-lait macules <ref name="Ratner">PMID:25877329</ref>, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is an essential protein and is involved mainly in the differentiation of neural crest-derived cells, mesenchymal cells, neural cells, melanocytes, and bone cells. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 mutations identified lead to a synthesis of truncated, non-functional protein and are a result of point mutations. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases de novo ones. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations of the gene NF1 can lead to major structural and functional changes that are dangerous for the patient. Here is the process of how a mutation could lead to life-threatening illnesses or conditions: If there is a mutation in the NF1 gene, this results in a loss of function of the Neurofibromin completely and/or the inability to interact with the Ras protein. If it cannot interact with Ras, there is no GTP to GDP, inactivating the Ras, meaning there is nothing that is limiting the Ras from promoting cell growth. Uncontrolled cell growth leads to tumors and patients are at a much higher risk for cancer. Mutations in NF1 have been found in sporadic cancers that are not even NF1 associated, which includes glioblastoma, neuroblastoma, lung cancer, ovarian cancer, and breast cancer. Additionally, NF1 is in the top ten genes that are most mutated in tumors of the lung, breast, ovary, pancreas, and prostate. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors. It is possible that the order of mutations affects the grade of a tumor for certain types of cells and thus explains why NF1 patients are not predisposed to certain types of sporadic tumors. <ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3536715 Sandbox Reserved 1710 2022-03-29T16:54:03Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation' scene='90/904315/Closed_spinning/2'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin.jpg|340 px|right|thumb|Surface Rendering of Neurofibromin in its Open and Closed Conformation]]<br /> Neurofibromin is a protein that is coded for by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 Gene] which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 by cryo-electron microscopy revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin is associated with diseases such as Plexiform Neurofibromas.<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/3'>homodimer</scene> made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and closed conformations, the <scene name='90/905640/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/2'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.<br /> <br /> === Closed Conformation ===<br /> The first conformation of Neurofibromin is known as the <scene name='90/904315/Closed/1'>Closed Conformation</scene>, which is representative of an inactive Neurofibromin protein. In the closed conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive due to a <scene name='90/904315/Catalytic_triade/1'>triade</scene> consisting of residues Cysteine 1032, Histidine 1558, and Histidine 1576 that form a transition metal-binding site with zinc. The close proximity of the C1032, H1558, and H1576 residues that form the <scene name='90/904316/Closed_triade/1'>triade in the closed conformation</scene> keep the GRD domain packed tightly on top of the Neurofibromin core. This tight compaction leads to steric inhibition when Neurofibromin tries to perform its function and associate with Ras. The association between Ras and Neurofibromin is supposed to occur via an <scene name='90/904316/Arg_finger/1'>Arginine Finger</scene> located at Residue 1276. However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, when Neurofibromin is in the closed conformation, there is no association with Ras and cell growth and proliferation is able to occur.<br /> <br /> === Open Conformation ===<br /> The other conformation that characterizes Neurofibromin is the <scene name='90/904315/Open_conformation/2'>Open Conformation</scene>. In the open conformation of Neurofibromin, the protein is considered active and is participating in its function of Ras regulation. This occurs because the transition metal-binding site with zinc no longer is able to form due to an increase in distance between the C1032, H1558 and H1576 residues that form the <scene name='90/904315/Open_conformation_triade/3'>Open Triade</scene>. One protomer in Neurofibromin has its GRD and Sec14-PH domains oriented in way that is almost reversed in position compared to the closed conformation. Due to this rotation, C1032 is now located too far away, approximately 30 Angstroms, from H1558 and H1576 which results in the loss of the metal-binding site. The lack of the transition metal-binding site allows the GRD to orient itself in such a way that it can associate with <scene name='90/904315/Ras_open_conformation/1'>Ras in the Open Conformation</scene>. The reason that Neurofibromin is only able to associate with Ras in the open conformation is due to one critical residue, the <scene name='90/904315/Open_conformation_arginine_fin/1'>Arginine Finger</scene> located at position 1276 in Neurofibromin. When Neurofibromin is in the open conformation, R1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/1'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:GRDandSec14PHRotation.jpg|340 px|left|thumb|Rotation of the GRD and Sec14-PH domains from the closed conformation of neurofibromin to the open conformation of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Function ==<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an Arginine finger (R1276) present in the GRD domain of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its Guanine triphosphatase-activating protein (GAP) activity; therefore, when there are mutations to the NF1 gene that prevent the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer.<ref name="Ratner">PMID:25877329</ref> [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called cafe-au-lait macules, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is an essential protein and is involved mainly in the differentiation of neural crest-derived cells, mesenchymal cells, neural cells, melanocytes, and bone cells. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 mutations identified lead to a synthesis of truncated, non-functional protein and are a result of point mutations. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases de novo ones. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations of the gene NF1 can lead to major structural and functional changes that are dangerous for the patient. Here is the process of how a mutation could lead to life-threatening illnesses or conditions: If there is a mutation in the NF1 gene, this results in a loss of function of the Neurofibromin completely and/or the inability to interact with the Ras protein. If it cannot interact with Ras, there is no GTP to GDP, inactivating the Ras, meaning there is nothing that is limiting the Ras from promoting cell growth. Uncontrolled cell growth leads to tumors and patients are at a much higher risk for cancer. Mutations in NF1 have been found in sporadic cancers that are not even NF1 associated, which includes glioblastoma, neuroblastoma, lung cancer, ovarian cancer, and breast cancer. Additionally, NF1 is in the top ten genes that are most mutated in tumors of the lung, breast, ovary, pancreas, and prostate. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors. It is possible that the order of mutations affects the grade of a tumor for certain types of cells and thus explains why NF1 patients are not predisposed to certain types of sporadic tumors. <ref name="Ratner">PMID:25877329</ref><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3536480 Sandbox Reserved 1710 2022-03-29T01:31:23Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation' scene='90/904315/Closed_spinning/2'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin.jpg|340 px|right|thumb|Surface Rendering of Neurofibromin in its Open and Closed Conformation]]<br /> Neurofibromin is a protein that is coded for by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 Gene] which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 by cryo-electron microscopy revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin is associated with diseases such as Plexiform Neurofibromas.<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/3'>homodimer</scene> made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and closed conformations, the <scene name='90/905640/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/2'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.<br /> <br /> === Closed Conformation ===<br /> The first conformation of Neurofibromin is known as the <scene name='90/904315/Closed/1'>Closed Conformation</scene>, which is representative of an inactive Neurofibromin protein. In the closed conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive due to a <scene name='90/904315/Catalytic_triade/1'>triade</scene> consisting of residues Cysteine 1032, Histidine 1558, and Histidine 1576 that form a transition metal-binding site with zinc. The close proximity of the C1032, H1558, and H1576 residues that form the <scene name='90/904316/Closed_triade/1'>triade in the closed conformation</scene> keep the GRD domain packed tightly on top of the Neurofibromin core. This tight compaction leads to steric inhibition when Neurofibromin tries to perform its function and associate with Ras. The association between Ras and Neurofibromin is supposed to occur via an <scene name='90/904316/Arg_finger/1'>Arginine Finger</scene> located at Residue 1276. However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, when Neurofibromin is in the closed conformation, there is no association with Ras and cell growth and proliferation is able to occur.<br /> <br /> === Open Conformation ===<br /> The other conformation that characterizes Neurofibromin is the <scene name='90/904315/Open_conformation/2'>Open Conformation</scene>. In the open conformation of Neurofibromin, the protein is considered active and is participating in its function of Ras regulation. This occurs because the transition metal-binding site with zinc no longer is able to form due to an increase in distance between the C1032, H1558 and H1576 residues that form the <scene name='90/904315/Open_conformation_triade/3'>Open Triade</scene>. One protomer in Neurofibromin has its GRD and Sec14-PH domains oriented in way that is almost reversed in position compared to the closed conformation. Due to this rotation, C1032 is now located too far away, approximately 30 Angstroms, from H1558 and H1576 which results in the loss of the metal-binding site. The lack of the transition metal-binding site allows the GRD to orient itself in such a way that it can associate with <scene name='90/904315/Ras_open_conformation/1'>Ras in the Open Conformation</scene>. The reason that Neurofibromin is only able to associate with Ras in the open conformation is due to one critical residue, the <scene name='90/904315/Open_conformation_arginine_fin/1'>Arginine Finger</scene> located at position 1276 in Neurofibromin. When Neurofibromin is in the open conformation, R1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/1'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:GRDandSec14PHRotation.jpg|340 px|left|thumb|Rotation of the GRD and Sec14-PH domains from the closed conformation of neurofibromin to the open conformation of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Function ==<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an Arginine finger (R1276) present in the GRD domain of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its Guanine triphosphatase-activating protein (GAP) activity; therefore, when there are mutations to the NF1 gene that prevent the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer.<ref name="Ratner">PMID:25877329</ref> [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called cafe-au-lait macules, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is an essential protein and is involved mainly in the differentiation of neural crest-derived cells, mesenchymal cells, neural cells, melanocytes, and bone cells. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 mutations identified lead to a synthesis of truncated, non-functional protein and are a result of point mutations. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases de novo ones. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> Mutations of the gene NF1 can lead to major structural and functional changes that are dangerous for the patient. Here is the process of how a mutation could lead to life-threatening illnesses or conditions: If there is a mutation in the NF1 gene, this results in a loss of function of the Neurofibromin completely and/or the inability to interact with the Ras protein. If it cannot interact with Ras, there is no GTP to GDP, inactivating the Ras, meaning there is nothing that is limiting the Ras from promoting cell growth. Uncontrolled cell growth leads to tumors and patients are at a much higher risk for cancer. Mutations in NF1 have been found in sporadic cancers that are not even NF1 associated, which includes glioblastoma, neuroblastoma, lung cancer, ovarian cancer, and breast cancer. Additionally, NF1 is in the top ten genes that are most mutated in tumors of the lung, breast, ovary, pancreas, and prostate. Researchers are still unsure as to whether biallelic loss of NF1 is common or if it is only a hemizygous loss of the gene that contributes to the growth progression of certain sporadic tumors. It is possible that the order of mutations affects the grade of a tumor for certain types of cells and thus explains why NF1 patients are not predisposed to certain types of sporadic tumors.<br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3536461 Sandbox Reserved 1710 2022-03-29T01:12:40Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation' scene='90/904315/Closed_spinning/2'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin.jpg|340 px|right|thumb|Surface Rendering of Neurofibromin in its Open and Closed Conformation]]<br /> Neurofibromin is a protein that is coded for by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 Gene] which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 by cryo-electron microscopy revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin is associated with diseases such as Plexiform Neurofibromas.<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/3'>homodimer</scene> made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and closed conformations, the <scene name='90/905640/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/2'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.<br /> <br /> === Closed Conformation ===<br /> The first conformation of Neurofibromin is known as the <scene name='90/904315/Closed/1'>Closed Conformation</scene>, which is representative of an inactive Neurofibromin protein. In the closed conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive due to a <scene name='90/904315/Catalytic_triade/1'>triade</scene> consisting of residues Cysteine 1032, Histidine 1558, and Histidine 1576 that form a transition metal-binding site with zinc. The close proximity of the C1032, H1558, and H1576 residues that form the <scene name='90/904316/Closed_triade/1'>triade in the closed conformation</scene> keep the GRD domain packed tightly on top of the Neurofibromin core. This tight compaction leads to steric inhibition when Neurofibromin tries to perform its function and associate with Ras. The association between Ras and Neurofibromin is supposed to occur via an <scene name='90/904316/Arg_finger/1'>Arginine Finger</scene> located at Residue 1276. However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, when Neurofibromin is in the closed conformation, there is no association with Ras and cell growth and proliferation is able to occur.<br /> <br /> === Open Conformation ===<br /> The other conformation that characterizes Neurofibromin is the <scene name='90/904315/Open_conformation/2'>Open Conformation</scene>. In the open conformation of Neurofibromin, the protein is considered active and is participating in its function of Ras regulation. This occurs because the transition metal-binding site with zinc no longer is able to form due to an increase in distance between the C1032, H1558 and H1576 residues that form the <scene name='90/904315/Open_conformation_triade/3'>Open Triade</scene>. One protomer in Neurofibromin has its GRD and Sec14-PH domains oriented in way that is almost reversed in position compared to the closed conformation. Due to this rotation, C1032 is now located too far away, approximately 30 Angstroms, from H1558 and H1576 which results in the loss of the metal-binding site. The lack of the transition metal-binding site allows the GRD to orient itself in such a way that it can associate with <scene name='90/904315/Ras_open_conformation/1'>Ras in the Open Conformation</scene>. The reason that Neurofibromin is only able to associate with Ras in the open conformation is due to one critical residue, the <scene name='90/904315/Open_conformation_arginine_fin/1'>Arginine Finger</scene> located at position 1276 in Neurofibromin. When Neurofibromin is in the open conformation, R1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/1'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:GRDandSec14PHRotation.jpg|340 px|left|thumb|Rotation of the GRD and Sec14-PH domains from the closed conformation of neurofibromin to the open conformation of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Function ==<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an Arginine finger (R1276) present in the GRD domain of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its Guanine triphosphatase-activating protein (GAP) activity; therefore, when there are mutations to the NF1 gene that prevent the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer.<ref name="Ratner">PMID:25877329</ref> [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called cafe-au-lait macules, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is an essential protein and is involved mainly in the differentiation of neural crest-derived cells, mesenchymal cells, neural cells, melanocytes, and bone cells. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 mutations identified lead to a synthesis of truncated, non-functional protein and are a result of point mutations. Type I Neurofibromatosis is inherited in an autosomal dominant manner but about 50% of cases de novo ones. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3536450 Sandbox Reserved 1710 2022-03-29T01:06:54Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation' scene='90/904315/Closed_spinning/2'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin.jpg|340 px|right|thumb|Surface Rendering of Neurofibromin in its Open and Closed Conformation]]<br /> Neurofibromin is a protein that is coded for by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 Gene] which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 by cryo-electron microscopy revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin is associated with diseases such as Plexiform Neurofibromas.<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/3'>homodimer</scene> made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and closed conformations, the <scene name='90/905640/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/2'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.<br /> <br /> === Closed Conformation ===<br /> The first conformation of Neurofibromin is known as the <scene name='90/904315/Closed/1'>Closed Conformation</scene>, which is representative of an inactive Neurofibromin protein. In the closed conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive due to a <scene name='90/904315/Catalytic_triade/1'>triade</scene> consisting of residues Cysteine 1032, Histidine 1558, and Histidine 1576 that form a transition metal-binding site with zinc. The close proximity of the C1032, H1558, and H1576 residues that form the <scene name='90/904316/Closed_triade/1'>triade in the closed conformation</scene> keep the GRD domain packed tightly on top of the Neurofibromin core. This tight compaction leads to steric inhibition when Neurofibromin tries to perform its function and associate with Ras. The association between Ras and Neurofibromin is supposed to occur via an <scene name='90/904316/Arg_finger/1'>Arginine Finger</scene> located at Residue 1276. However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, when Neurofibromin is in the closed conformation, there is no association with Ras and cell growth and proliferation is able to occur.<br /> <br /> === Open Conformation ===<br /> The other conformation that characterizes Neurofibromin is the <scene name='90/904315/Open_conformation/2'>Open Conformation</scene>. In the open conformation of Neurofibromin, the protein is considered active and is participating in its function of Ras regulation. This occurs because the transition metal-binding site with zinc no longer is able to form due to an increase in distance between the C1032, H1558 and H1576 residues that form the <scene name='90/904315/Open_conformation_triade/3'>Open Triade</scene>. One protomer in Neurofibromin has its GRD and Sec14-PH domains oriented in way that is almost reversed in position compared to the closed conformation. Due to this rotation, C1032 is now located too far away, approximately 30 Angstroms, from H1558 and H1576 which results in the loss of the metal-binding site. The lack of the transition metal-binding site allows the GRD to orient itself in such a way that it can associate with <scene name='90/904315/Ras_open_conformation/1'>Ras in the Open Conformation</scene>. The reason that Neurofibromin is only able to associate with Ras in the open conformation is due to one critical residue, the <scene name='90/904315/Open_conformation_arginine_fin/1'>Arginine Finger</scene> located at position 1276 in Neurofibromin. When Neurofibromin is in the open conformation, R1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/1'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:GRDandSec14PHRotation.jpg|340 px|left|thumb|Rotation of the GRD and Sec14-PH domains from the closed conformation of neurofibromin to the open conformation of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Function ==<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation of Neurofibromin. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an arginine finger (R1276) present in the GRD of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains of Neurofibromin are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its guanine triphosphatase-activating protein (GAP) activity, therefore when there are mutations to the NF1 gene that prevents the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer.<ref name="Ratner">PMID:25877329</ref> [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called cafe au lait macules, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is an essential protein and is involved mainly in the differentiation of neural crest derived cells, mesenchymal cells, neural cells, melanocytes, and bone cells. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 mutations identified lead to a synthesis of truncated, non-functional protein and are a result of point mutations. Type I Neurofibromatosis is inherited in autosomal dominant manner but about 50% of cases de novo ones. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3536441 Sandbox Reserved 1710 2022-03-29T01:02:18Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation' scene='90/904315/Closed_spinning/2'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin.jpg|340 px|right|thumb|Surface Rendering of Neurofibromin in its Open and Closed Conformation]]<br /> Neurofibromin is a protein that is coded for by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 Gene] which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 by cryo-electron microscopy revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin is associated with diseases such as Plexiform Neurofibromas.<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/3'>homodimer</scene> made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and closed conformations, the <scene name='90/905640/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/2'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.<br /> <br /> === Closed Conformation ===<br /> The first conformation of Neurofibromin is known as the <scene name='90/904315/Closed/1'>Closed Conformation</scene>, which is representative of an inactive Neurofibromin protein. In the closed conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive due to a <scene name='90/904315/Catalytic_triade/1'>triade</scene> consisting of residues Cysteine 1032, Histidine 1558, and Histidine 1576 that form a transition metal-binding site with zinc. The close proximity of the C1032, H1558, and H1576 residues that form the <scene name='90/904316/Closed_triade/1'>triade in the closed conformation</scene> keep the GRD domain packed tightly on top of the Neurofibromin core. This tight compaction leads to steric inhibition when Neurofibromin tries to perform its function and associate with Ras. The association between Ras and Neurofibromin is supposed to occur via an <scene name='90/904316/Arg_finger/1'>Arginine Finger</scene> located at Residue 1276. However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, when Neurofibromin is in the closed conformation, there is no association with Ras and cell growth and proliferation is able to occur.<br /> <br /> === Open Conformation ===<br /> The other conformation that characterizes Neurofibromin is the <scene name='90/904315/Open_conformation/2'>Open Conformation</scene>. In the open conformation of Neurofibromin, the protein is considered active and is participating in its function of Ras regulation. This occurs because the transition metal-binding site with zinc no longer is able to form due to an increase in distance between the C1032, H1558 and H1576 residues that form the <scene name='90/904315/Open_conformation_triade/3'>Open Triade</scene>. One protomer in Neurofibromin has its GRD and Sec14-PH domains oriented in way that is almost reversed in position compared to the closed conformation. Due to this rotation, C1032 is now located too far away, approximately 30 Angstroms, from H1558 and H1576 which results in the loss of the metal-binding site. The lack of the transition metal-binding site allows the GRD to orient itself in such a way that it can associate with <scene name='90/904315/Ras_open_conformation/1'>Ras in the Open Conformation</scene>. The reason that Neurofibromin is only able to associate with Ras in the open conformation is due to one critical residue, the <scene name='90/904315/Open_conformation_arginine_fin/1'>Arginine Finger</scene> located at position 1276 in Neurofibromin. When Neurofibromin is in the open conformation, R1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/1'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:GRDandSec14PHRotation.jpg|340 px|left|thumb|Rotation of the GRD and Sec14-PH domains from the closed conformation of neurofibromin to the open conformation of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Function ==<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an arginine finger (R1276) present in the GRD of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains of Neurofibromin are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its guanine triphosphatase-activating protein (GAP) activity, therefore when there are mutations to the NF1 gene that prevents the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer.<ref name="Ratner">PMID:25877329</ref> [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called cafe au lait macules, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is an essential protein and is involved mainly in the differentiation of neural crest derived cells, mesenchymal cells, neural cells, melanocytes, and bone cells. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 mutations identified lead to a synthesis of truncated, non-functional protein and are a result of point mutations. Type I Neurofibromatosis is inherited in autosomal dominant manner but about 50% of cases de novo ones. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1710&diff=3536437 Sandbox Reserved 1710 2022-03-29T00:57:23Z

<p>Sophie Mullinix: </p> <hr /> <div>{{Template:CH462_Biochemistry_II_2022}}<br /> = Human Neurofibromin - The Tumor Suppressor Gene =<br /> <br /> <StructureSection load='' size='340' side='right' caption='Neurofibromin in the Closed Conformation' scene='90/904315/Closed_spinning/2'><br /> <br /> == Introduction ==<br /> [[Image:Neurofibromin.jpg|340 px|right|thumb|Surface Rendering of Neurofibromin in its Open and Closed Conformation]]<br /> Neurofibromin is a protein that is coded for by the [https://en.wikipedia.org/wiki/Neurofibromin_1 NF1 Gene] which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras. The molecular structure of Neurofibromin has been determined by [https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryo-Electron Microscopy]. The structure of neurofibromin isoform 2 by cryo-electron microscopy revealed different functional states for the Neurofibromin protein.<ref name="Naschberger">PMID:34707296</ref> Mutations in Neurofibromin is associated with diseases such as Plexiform Neurofibromas.<br /> <br /> == Structure ==<br /> Neurofibromin is a <scene name='90/904315/Homodimer/3'>homodimer</scene> made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and closed conformations, the <scene name='90/905640/Grd_domains/2'>GRD</scene> domain and the <scene name='90/904315/Sec14ph_domain/2'>Sec14-PH</scene> domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.<br /> <br /> === Closed Conformation ===<br /> The first conformation of Neurofibromin is known as the <scene name='90/904315/Closed/1'>Closed Conformation</scene>, which is representative of an inactive Neurofibromin protein. In the closed conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive due to a <scene name='90/904315/Catalytic_triade/1'>triade</scene> consisting of residues cysteine 1032, histidine 1558, and histidine 1576 that form a transition metal-binding site with zinc. The close proximity of the C1032, H1558, and H1576 residues that form the <scene name='90/904316/Closed_triade/1'>triade in the closed conformation</scene> keep the GRD domain packed tightly on top of the Neurofibromin core. This tight compaction leads to steric inhibition when Neurofibromin tries to perform its function and associate with Ras. The association between Ras and Neurofibromin is supposed to occur via an <scene name='90/904316/Arg_finger/1'>Arginine Finger</scene> located at Residue 1276. However, the steric hindrance from the Neurofibromin core in the closed conformation inhibits this association. Therefore, when Neurofibromin is in the closed conformation, there is no association with Ras and cell growth and proliferation is able to occur.<br /> <br /> === Open Conformation ===<br /> The other conformation that characterizes Neurofibromin is the <scene name='90/904315/Open_conformation/2'>Open Conformation</scene>. In the open conformation of Neurofibromin, the protein is considered active and is participating in its function of Ras regulation. This occurs because the transition metal-binding site with zinc no longer is able to form due to an increase in distance between the C1032, H1558 and H1576 residues that form the <scene name='90/904315/Open_conformation_triade/3'>Open Triade</scene>. One protomer in Neurofibromin has its GRD and Sec14-PH domains oriented in way that is almost reversed in position compared to the closed conformation. Due to this rotation, C1032 is now located too far away, approximately 30 Angstroms, from H1558 and H1576 which results in the loss of the metal-binding site. The lack of the transition metal-binding site allows the GRD to orient itself in such a way that it can associate with <scene name='90/904315/Ras_open_conformation/1'>Ras in the Open Conformation</scene>. The reason that Neurofibromin is only able to associate with Ras in the open conformation is due to one critical residue, the <scene name='90/904315/Open_conformation_arginine_fin/1'>Arginine Finger</scene> located at position 1276 in Neurofibromin. When Neurofibromin is in the open conformation, R1276 is able to <scene name='90/904315/Ras_open_conformation_with_arg/1'>bind to Ras</scene> because there is no steric hindrance from the Neurofibromin core.<br /> <br /> [[Image:GRDandSec14PHRotation.jpg|340 px|left|thumb|Rotation of the GRD and Sec14-PH domains from the closed conformation of neurofibromin to the open conformation of neurofibromin to allow Ras binding. The GRD rotates -130° and the Sec14-PH domain rotates -90°]]<br /> <br /> == Function ==<br /> Neurofibromin functions as a tumor suppressor protein.<ref name="Trovó-Marqui">PMID:16813595</ref> Its job is to prevent cell growth by turning off another protein known as [https://en.wikipedia.org/wiki/Ras_GTPase Ras] which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as [https://medlineplus.gov/genetics/gene/spred1/ SPRED1]. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an arginine finger (R1276) present in the GRD of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains of Neurofibromin are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the [https://en.wikipedia.org/wiki/MAPK/ERK_pathway Ras signaling pathway] by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.<br /> [[Image:mechanismofRas.png|340 px|right|thumb|Mechanism of Ras Regulation by Neurofibromin]]<br /> <br /> == Disease and Medical Relevance ==<br /> Currently, there are over 1485 mutations of Neurofibromin that have been identified. Mutations in Neurofibromin can lead to life-threatening illnesses or conditions such as Neurofibromatosis Type I due to the inability of Neurofibromin to interact with Ras.<ref name="Lupton">PMID: 34887559 </ref> The role of Neurofibromin is to inhibit cellular proliferation via its guanine triphosphatase-activating protein (GAP) activity, therefore when there are mutations to the NF1 gene that prevents the interaction of Neufibromin with Ras, there is nothing stopping Ras from promoting cell growth. Uncontrolled cell growth can lead to tumors and a higher risk of cancer.<ref name="Ratner">PMID:25877329</ref> [https://medlineplus.gov/genetics/condition/neurofibromatosis-type-1/ Neurofibromatosis Type 1], the most well-known disease resulting from mutations in Neurofibromin, is characterized by cognitive impairment, soft, non-cancerous tumors on or under the skin known as neurofibromas, birthmarks called cafe au lait macules, clusters of freckles in unusual places, and problems with the bones, eyes and nervous system.<br /> <br /> Neurofibromin is an essential protein and is involved mainly in the differentiation of neural crest derived cells, mesenchymal cells, neural cells, melanocytes, and bone cells. As Neurofibromin is essential for embryonic development, mutations to the NF1 gene can result in psychological retardation resulting from Type I neurofibromatosis. Most of the 1485 mutations identified lead to a synthesis of truncated, non-functional protein and are a result of point mutations. Type I Neurofibromatosis is inherited in autosomal dominant manner but about 50% of cases de novo ones. <ref name="Abramowicz">PMID:25182393</ref> <br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski<br /> *Sophie Mullinix<br /> <br /> </StructureSection><br /> == References ==<br /> <references/></div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1711&diff=3536252 Sandbox Reserved 1711 2022-03-28T20:12:29Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> Neurofibromin is a <scene name='90/905640/Homodimer/1'>homodimer</scene> with two identical chains (depicted as lime and cyan).<br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> In the overall <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene> (and inactive) conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive. The closed conformation has both of the protomers/chains in the closed positions, whereas the open conformation has one closed and one open protomer. You can see that in the closed conformation, Ras binding by the GRD domain is sterically hindered and there is no room for association with the Ras protein. <br /> The closed conformation has the GRD and Sec14-PH domains oriented in a way that the amino acids C1032, H1558, and H1576 are in close proximity to each other to form a transition metal-binding site with zinc. The fourth coordination partner in this is water. <br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene> <br /> <br /> === Domains ===<br /> The <scene name='90/905640/Grd_domains/2'>GRD domain</scene> of Neurofibromin, specifically the arginine finger (R1276), binds to the Ras + GTP complex.<br /> === Key Players ===<br /> An <scene name='90/905640/Arg_finger/1'>R1276</scene> (R1276) <scene name='90/904316/Arg_finger/1'>R1276</scene> present in the GRD is critical for Ras binding and is only accessible when the GRD and Sec14-PH domains are rotated in such a way that there is no steric hindrance from the surrounding dimer chains. The Closed conformation is stabilized by a <scene name='90/904316/Closed_triade/1'>triade</scene> of residues that are coordinated with transition metal-binding sites with zinc. Here, the GRD and Sec14-PH domains are oriented in a way that the H1558 and H1576 are able to interact with C1032 and form a transition binding-site with zinc. This binding site stabilizes the closed conformation and prevents Ras from associating with the GRD based on the location of the GRD in relation to the rest of the protein. <br /> == Function ==<br /> The GRD arginine finger (R1276) is crucial in Ras binding. When Neurofibromin is in the open conformation, the Arginine finger is able to bind with Ras because the Arginine is not inhibited as it would be in the closed conformation, where R1276 is facing the core and inaccessible due to the rotation of the two domains. This open conformation allows neurofibromin to associate with Ras via R1276 binding, which then hydrolyzes the Ras from active GTP to inactive GDP, showing why R1276 is crucial to neurofibromin function. In the open conformation, on the other hand, the arginine finger is able to interact with Ras and hydrolyze it which effectively turns it off. <br /> === Ras Control ===<br /> Ras is still promoting cell proliferation in this closed conformation because Neurofibromin is unable to hydrolyze Ras and inactivate it. In this open conformation, the Ras is not sterically hindered and the Arginine finger is accessible for Ras binding, thus allowing Neurofibromin to down-regulate Ras.<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1711&diff=3536224 Sandbox Reserved 1711 2022-03-28T19:40:08Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> Neurofibromin is a <scene name='90/905640/Homodimer/1'>homodimer</scene> with two identical chains (depicted as lime and cyan).<br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> In the overall <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene> (and inactive) conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive. The closed conformation has both of the protomers/chains in the closed positions, whereas the open conformation has one closed and one open protomer. You can see that in the closed conformation, Ras binding by the GRD domain is sterically hindered and there is no room for association with the Ras protein. <br /> The closed conformation has the GRD and Sec14-PH domains oriented in a way that the amino acids C1032, H1558, and H1576 are in close proximity to each other to form a transition metal-binding site with zinc. The fourth coordination partner in this is water. <br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene> <br /> <br /> === Domains ===<br /> The <scene name='90/905640/Grd_domains/2'>GRD domain</scene> of Neurofibromin, specifically the arginine finger (R1276), binds to the Ras + GTP complex.<br /> === Key Players ===<br /> An <scene name='90/905640/Arg_finger/1'>R1276</scene> (R1276) <scene name='90/904316/Arg_finger/1'>R1276</scene> present in the GRD is critical for Ras binding and is only accessible when the GRD and Sec14-PH domains are rotated in such a way that there is no steric hindrance from the surrounding dimer chains. The Closed conformation is stabilized by a triade of residues that are coordinated with transition metal-binding sites with zinc. Here, the GRD and Sec14-PH domains are oriented in a way that the H1558 and H1576 are able to interact with C1032 and form a transition binding-site with zinc. This binding site stabilizes the closed conformation and prevents Ras from associating with the GRD based on the location of the GRD in relation to the rest of the protein. <br /> == Function ==<br /> The GRD arginine finger (R1276) is crucial in Ras binding. When Neurofibromin is in the open conformation, the Arginine finger is able to bind with Ras because the Arginine is not inhibited as it would be in the closed conformation, where R1276 is facing the core and inaccessible due to the rotation of the two domains. This open conformation allows neurofibromin to associate with Ras via R1276 binding, which then hydrolyzes the Ras from active GTP to inactive GDP, showing why R1276 is crucial to neurofibromin function. In the open conformation, on the other hand, the arginine finger is able to interact with Ras and hydrolyze it which effectively turns it off. <br /> === Ras Control ===<br /> Ras is still promoting cell proliferation in this closed conformation because Neurofibromin is unable to hydrolyze Ras and inactivate it. In this open conformation, the Ras is not sterically hindered and the Arginine finger is accessible for Ras binding, thus allowing Neurofibromin to down-regulate Ras.<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1711&diff=3536211 Sandbox Reserved 1711 2022-03-28T19:26:15Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> Neurofibromin is a <scene name='90/905640/Homodimer/1'>homodimer</scene> with two identical chains (depicted as lime and cyan).<br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> In the overall <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene> (and inactive) conformation, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive. The closed conformation has both of the protomers/chains in the closed positions, whereas the open conformation has one closed and one open protomer. You can see that in the closed conformation, Ras binding by the GRD domain is sterically hindered and there is no room for association with the Ras protein. <br /> The closed conformation has the GRD and Sec14-PH domains oriented in a way that the amino acids C1032, H1558, and H1576 are in close proximity to each other to form a transition metal-binding site with zinc. The fourth coordination partner in this is water. <br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene> <br /> <br /> === Domains ===<br /> The <scene name='90/905640/Grd_domains/2'>GRD domain</scene> of Neurofibromin, specifically the arginine finger (R1276), binds to the Ras + GTP complex.<br /> === Key Players ===<br /> An <scene name='90/905640/Arg_finger/1'>R1276</scene> (R1276) present in the GRD is critical for Ras binding and is only accessible when the GRD and Sec14-PH domains are rotated in such a way that there is no steric hindrance from the surrounding dimer chains. The Closed conformation is stabilized by a triade of residues that are coordinated with transition metal-binding sites with zinc. Here, the GRD and Sec14-PH domains are oriented in a way that the H1558 and H1576 are able to interact with C1032 and form a transition binding-site with zinc. This binding site stabilizes the closed conformation and prevents Ras from associating with the GRD based on the location of the GRD in relation to the rest of the protein. <br /> == Function ==<br /> The GRD arginine finger (R1276) is crucial in Ras binding. When Neurofibromin is in the open conformation, the Arginine finger is able to bind with Ras because the Arginine is not inhibited as it would be in the closed conformation, where R1276 is facing the core and inaccessible due to the rotation of the two domains. This open conformation allows neurofibromin to associate with Ras via R1276 binding, which then hydrolyzes the Ras from active GTP to inactive GDP, showing why R1276 is crucial to neurofibromin function. In the open conformation, on the other hand, the arginine finger is able to interact with Ras and hydrolyze it which effectively turns it off. <br /> === Ras Control ===<br /> Ras is still promoting cell proliferation in this closed conformation because Neurofibromin is unable to hydrolyze Ras and inactivate it. In this open conformation, the Ras is not sterically hindered and the Arginine finger is accessible for Ras binding, thus allowing Neurofibromin to down-regulate Ras.<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1711&diff=3536208 Sandbox Reserved 1711 2022-03-28T19:20:46Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> Neurofibromin is a <scene name='90/905640/Homodimer/1'>homodimer</scene> with two identical chains (depicted as lime and cyan).<br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> In the overall closed <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene> and inactive conformation of the neurofibromin protein, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive. The closed conformation has both protomers/chains in the closed structure, whereas the open conformation has one closed and one open protomer. You can see that in the closed conformation, Ras binding by the GRD domain is sterically hindered and there is no room for association with the Ras protein. <br /> The closed conformation has the GRD and Sec14-PH domains oriented in a way that the amino acids C1032, H1558, and H1576 are in close proximity to each other to form a transition metal-binding site with zinc. The fourth coordination partner in this is water. <br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene> <br /> <br /> === Domains ===<br /> The <scene name='90/905640/Grd_domains/2'>GRD domain</scene> of Neurofibromin, specifically the arginine finger (R1276), binds to the Ras + GTP complex.<br /> === Key Players ===<br /> This is because an <scene name='90/905640/Arg_finger/1'>R1276</scene> (R1276) present in the GRD is critical for Ras binding and is only accessible when the GRD and Sec14-PH domains are rotated in such a way that there is no steric hindrance from the surrounding dimer chains. The Closed conformation is stabilized by a triade of residues that are coordinated with transition metal-binding sites with zinc. Here, the GRD and Sec14-PH domains are oriented in a way that the H1558 and H1576 are able to interact with C1032 and form a transition binding-site with zinc. This binding site stabilizes the closed conformation and prevents Ras from associating with the GRD based on the location of the GRD in relation to the rest of the protein. <br /> == Function ==<br /> <br /> === Ras Control ===<br /> Ras is still promoting cell proliferation in this closed conformation because Neurofibromin is unable to hydrolyze Ras and inactivate it. In this open conformation, the Ras is not sterically hindered and the Arginine finger is accessible for Ras binding, thus allowing Neurofibromin to down-regulate Ras.<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_Reserved_1711&diff=3536201 Sandbox Reserved 1711 2022-03-28T19:10:58Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> Neurofibromin is a <scene name='90/905640/Homodimer/1'>homodimer</scene> with two identical chains (depicted as lime and cyan).<br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> In the overall closed <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene> and inactive conformation of the neurofibromin protein, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive. The closed conformation has both protomers/chains in the closed structure, whereas the open conformation has one closed and one open protomer. You can see that in the closed conformation, Ras binding by the GRD domain is sterically hindered and there is no room for association with the Ras protein. <br /> The closed conformation has the GRD and Sec14-PH domains oriented in a way that the amino acids C1032, H1558, and H1576 are in close proximity to each other to form a transition metal-binding site with zinc. The fourth coordination partner in this is water. <br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene> <br /> <br /> === Domains ===<br /> The <scene name='90/905640/Grd_domains/2'>GRD domain</scene> of Neurofibromin, specifically the arginine finger (R1276), binds to the Ras + GTP complex.<br /> === Key Players ===<br /> This is because an <scene name='90/905640/Arg_finger/1'>R1276</scene> (R1276) present in the GRD is critical for Ras binding and is only accessible when the GRD and Sec14-PH domains are rotated in such a way that there is no steric hindrance from the surrounding dimer chains. <br /> Closed conformation is stabilized by one cysteine and two histidines that are coordinated with transition metal-binding sites with zinc. <br /> == Function ==<br /> <br /> === Ras Control ===<br /> Ras is still promoting cell proliferation in this closed conformation because Neurofibromin is unable to hydrolyze Ras and inactivate it. In this open conformation, the Ras is not sterically hindered and the Arginine finger is accessible for Ras binding, thus allowing Neurofibromin to down-regulate Ras.<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=User:Sophie_Mullinix/Sandbox1711&diff=3536199 User:Sophie Mullinix/Sandbox1711 2022-03-28T19:09:19Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> Neurofibromin is a <scene name='90/905640/Homodimer/1'>homodimer</scene> with two identical chains (depicted as lime and cyan).<br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> In the overall closed <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene> and inactive conformation of the neurofibromin protein, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive. The closed conformation has both protomers/chains in the closed structure, whereas the open conformation has one closed and one open protomer. You can see that in the closed conformation, Ras binding by the GRD domain is sterically hindered and there is no room for association with the Ras protein. <br /> The closed conformation has the GRD and Sec14-PH domains oriented in a way that the amino acids C1032, H1558, and H1576 are in close proximity to each other to form a transition metal-binding site with zinc. The fourth coordination partner in this is water. <br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene> <br /> <br /> === Domains ===<br /> The <scene name='90/905640/Grd_domains/2'>GRD domain</scene> of Neurofibromin, specifically the arginine finger (R1276), binds to the Ras + GTP complex.<br /> === Key Players ===<br /> This is because an <scene name='90/905640/Arg_finger/1'>R1276</scene> (R1276) present in the GRD is critical for Ras binding and is only accessible when the GRD and Sec14-PH domains are rotated in such a way that there is no steric hindrance from the surrounding dimer chains. <br /> Closed conformation is stabilized by one cysteine and two histidines that are coordinated with transition metal-binding sites with zinc. <br /> == Function ==<br /> <br /> === Ras Control ===<br /> Ras is still promoting cell proliferation in this closed conformation because Neurofibromin is unable to hydrolyze Ras and inactivate it. In this open conformation, the Ras is not sterically hindered and the Arginine finger is accessible for Ras binding, thus allowing Neurofibromin to down-regulate Ras.<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=User:Sophie_Mullinix/Sandbox1&diff=3536196 User:Sophie Mullinix/Sandbox1 2022-03-28T19:06:28Z

<p>Sophie Mullinix: User:Sophie Mullinix/Sandbox1 moved to Sandbox 1711</p> <hr /> <div>#REDIRECT [[Sandbox 1711]]</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_1711&diff=3536195 Sandbox 1711 2022-03-28T19:06:28Z

<p>Sophie Mullinix: User:Sophie Mullinix/Sandbox1 moved to Sandbox 1711</p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> Neurofibromin is a <scene name='90/905640/Homodimer/1'>homodimer</scene> with two identical chains (depicted as lime and cyan).<br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> In the overall closed <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene> and inactive conformation of the neurofibromin protein, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive. The closed conformation has both protomers/chains in the closed structure, whereas the open conformation has one closed and one open protomer. You can see that in the closed conformation, Ras binding by the GRD domain is sterically hindered and there is no room for association with the Ras protein. <br /> The closed conformation has the GRD and Sec14-PH domains oriented in a way that the amino acids C1032, H1558, and H1576 are in close proximity to each other to form a transition metal-binding site with zinc. The fourth coordination partner in this is water. <br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene> <br /> <br /> === Domains ===<br /> The <scene name='90/905640/Grd_domains/2'>GRD domain</scene> of Neurofibromin, specifically the arginine finger (R1276), binds to the Ras + GTP complex.<br /> === Key Players ===<br /> This is because an <scene name='90/905640/Arg_finger/1'>R1276</scene> (R1276) present in the GRD is critical for Ras binding and is only accessible when the GRD and Sec14-PH domains are rotated in such a way that there is no steric hindrance from the surrounding dimer chains. <br /> Closed conformation is stabilized by one cysteine and two histidines that are coordinated with transition metal-binding sites with zinc. <br /> == Function ==<br /> <br /> === Ras Control ===<br /> Ras is still promoting cell proliferation in this closed conformation because Neurofibromin is unable to hydrolyze Ras and inactivate it. In this open conformation, the Ras is not sterically hindered and the Arginine finger is accessible for Ras binding, thus allowing Neurofibromin to down-regulate Ras.<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_1711&diff=3536194 Sandbox 1711 2022-03-28T19:05:30Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> Neurofibromin is a <scene name='90/905640/Homodimer/1'>homodimer</scene> with two identical chains (depicted as lime and cyan).<br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> In the overall closed <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene> and inactive conformation of the neurofibromin protein, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive. The closed conformation has both protomers/chains in the closed structure, whereas the open conformation has one closed and one open protomer. You can see that in the closed conformation, Ras binding by the GRD domain is sterically hindered and there is no room for association with the Ras protein. <br /> The closed conformation has the GRD and Sec14-PH domains oriented in a way that the amino acids C1032, H1558, and H1576 are in close proximity to each other to form a transition metal-binding site with zinc. The fourth coordination partner in this is water. <br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene> <br /> <br /> === Domains ===<br /> The <scene name='90/905640/Grd_domains/2'>GRD domain</scene> of Neurofibromin, specifically the arginine finger (R1276), binds to the Ras + GTP complex.<br /> === Key Players ===<br /> This is because an <scene name='90/905640/Arg_finger/1'>R1276</scene> (R1276) present in the GRD is critical for Ras binding and is only accessible when the GRD and Sec14-PH domains are rotated in such a way that there is no steric hindrance from the surrounding dimer chains. <br /> Closed conformation is stabilized by one cysteine and two histidines that are coordinated with transition metal-binding sites with zinc. <br /> == Function ==<br /> <br /> === Ras Control ===<br /> Ras is still promoting cell proliferation in this closed conformation because Neurofibromin is unable to hydrolyze Ras and inactivate it. In this open conformation, the Ras is not sterically hindered and the Arginine finger is accessible for Ras binding, thus allowing Neurofibromin to down-regulate Ras.<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_1711&diff=3536003 Sandbox 1711 2022-03-28T03:36:25Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> Neurofibromin is a <scene name='90/905640/Homodimer/1'>homodimer</scene> with two identical chains (depicted as lime and cyan).<br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> In the overall closed <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene> and inactive conformation of the neurofibromin protein, both sets of the GRD and Sec14-PH domains are rotated in a way that they are inaccessible and inactive. The closed conformation is much more tightly compacted and there is no room for association with the Ras protein.<br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene><br /> === Domains ===<br /> <scene name='90/905640/Grd_domains/2'>GRD domain</scene><br /> === Key Players ===<br /> <scene name='90/905640/Arg_finger/1'>R1276</scene><br /> <br /> == Function ==<br /> <br /> === Ras Control ===<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_1711&diff=3536002 Sandbox 1711 2022-03-28T03:32:34Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> Neurofibromin is a <scene name='90/905640/Homodimer/1'>homodimer</scene> with two identical chains (depicted as lime and cyan).<br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene><br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene><br /> === Domains ===<br /> <scene name='90/905640/Grd_domains/2'>GRD domain</scene><br /> === Key Players ===<br /> <scene name='90/905640/Arg_finger/1'>R1276</scene><br /> <br /> == Function ==<br /> <br /> === Ras Control ===<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_1711&diff=3532820 Sandbox 1711 2022-03-22T20:25:30Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> <scene name='90/905640/Homodimer/1'>homodimer</scene><br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene><br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene><br /> === Domains ===<br /> <scene name='90/905640/Grd_domains/2'>GRD domain</scene><br /> === Key Players ===<br /> <scene name='90/905640/Arg_finger/1'>R1276</scene><br /> <br /> == Function ==<br /> <br /> === Ras Control ===<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_1711&diff=3532803 Sandbox 1711 2022-03-22T20:00:13Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> <scene name='90/905640/Homodimer/1'>homodimer</scene><br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene><br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene><br /> === Domains ===<br /> <scene name='90/905640/Grd_domains/2'>GRD domain</scene><br /> === Key Players ===<br /> <br /> == Function ==<br /> <br /> === Ras Control ===<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_1711&diff=3532798 Sandbox 1711 2022-03-22T19:55:39Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> <scene name='90/905640/Homodimer/1'>homodimer</scene><br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene><br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene><br /> === Domains ===<br /> <scene name='90/905640/Grd_domains/1'>GRD domains</scene><br /> === Key Players ===<br /> <br /> == Function ==<br /> <br /> === Ras Control ===<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_1711&diff=3532790 Sandbox 1711 2022-03-22T19:40:08Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> <scene name='90/905640/Homodimer/1'>homodimer</scene><br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene><br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene><br /> === Domains ===<br /> === Key Players ===<br /> <br /> == Function ==<br /> <br /> === Ras Control ===<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_1711&diff=3532783 Sandbox 1711 2022-03-22T19:27:05Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> <br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> <scene name='90/905640/Closedoverall/1'>closed neurofibromin</scene><br /> <scene name='90/905640/Closedoverall/6'>vertical view</scene><br /> === Domains ===<br /> === Key Players ===<br /> <br /> == Function ==<br /> <br /> === Ras Control ===<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_1711&diff=3532782 Sandbox 1711 2022-03-22T19:25:30Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='90/905640/Closedoverall/1'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> <br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> <scene name='90/905640/Closedoverall/1'>closedoverall</scene><br /> <scene name='90/905640/Closedoverall/6'>birdseyeview</scene><br /> === Domains ===<br /> === Key Players ===<br /> <br /> == Function ==<br /> <br /> === Ras Control ===<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_1711&diff=3532780 Sandbox 1711 2022-03-22T19:24:44Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='Closedoverall'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> <br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> <scene name='90/905640/Closedoverall/1'>closedoverall</scene><br /> <scene name='90/905640/Closedoverall/6'>birdseyeview</scene><br /> === Domains ===<br /> === Key Players ===<br /> <br /> == Function ==<br /> <br /> === Ras Control ===<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_1711&diff=3532777 Sandbox 1711 2022-03-22T19:17:47Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin: Ras Regulator =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='closedoverall'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> <br /> === Conformation: Open ===<br /> <br /> === Conformation: Closed ===<br /> <scene name='90/905640/Closedoverall/1'>closedoverall</scene><br /> <scene name='90/905640/Closedoverall/6'>birdseyeview</scene><br /> === Domains ===<br /> === Key Players ===<br /> <br /> == Function ==<br /> <br /> === Ras Control ===<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix https://proteopedia.org/index.php?title=Sandbox_1711&diff=3532776 Sandbox 1711 2022-03-22T19:17:02Z

<p>Sophie Mullinix: </p> <hr /> <div>= Neurofibromin: Ras Regulator =<br /> <br /> <StructureSection load='7pgr' size='340' side='right' caption='Closed conformation of Neurofibromin' scene='closedoverall'><br /> <br /> ---<br /> <br /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692384/]<br /> <br /> [[Image:Open.jpg|400px|right|thumb|Figure_1]]<br /> <br /> == Introduction ==<br /> <ref name="Bergoug">PMID:33121128</ref><br /> == Structure ==<br /> <br /> === Conformation: Open ===<br /> <br /> <scene name='90/905640/Histohis/2'>H1558-H1576</scene><br /> === Conformation: Closed ===<br /> <scene name='90/905640/Closedoverall/1'>closedoverall</scene><br /> <scene name='90/905640/Closedoverall/6'>birdseyeview</scene><br /> === Domains ===<br /> === Key Players ===<br /> <br /> == Function ==<br /> <br /> === Ras Control ===<br /> === Mutated ===<br /> <br /> == Diseases ==<br /> <ref name="Ransey">PMID:28504306</ref><br /> <br /> <br /> <br /> </StructureSection><br /> == References ==<br /> <references/><br /> <br /> == Student Contributors ==<br /> *Hannah Luchinski</div>

Sophie Mullinix