Sandbox Reserved 1710: Difference between revisions
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=== Closed Conformation === | === Closed Conformation === | ||
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 <scene name='90/904315/Closed_with_ras/2'>associating with Ras.</scene> In its active form, Ras and Neurofibromin will associate via an (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> | 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 <scene name='90/904315/Closed_with_ras/2'>associating with Ras.</scene> In its active form, Ras and Neurofibromin will associate via an Arginine Finger(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> | ||
=== Open Conformation === | === Open Conformation === | ||
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 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 (Figure 4). 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 | 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 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 (Figure 4). 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 <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/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> | ||
[[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°]] | [[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°]] | ||
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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> | 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> | ||
== Student Contributors == | == Student Contributors == | ||
