Neurofibromin: Difference between revisions

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Neurofibromin is a cytoplasmic protein located close to the cell membrane that is encoded by the ''NF1'' gene located on chromosome 17 <ref name= ''Bergoug''>PMID:33121128</ref>. It is a suppressor of the [http://https://www.cancer.gov/publications/dictionaries/cancer-terms/def/ras-gene-family Ras] oncogene through its effect on the rate of catalysis from <scene name='90/904325/Ras_full_structure/2'>Ras-GTP</scene> (active) to Ras-GDP (inactive)<ref name= ''Hall''>PMID:12213964</ref>. NF increasing the rate of catalysis of Ras means that Ras spends more time in its inactive state and cannot cause unnecessary cell proliferation linked to cancer<ref name= ''Cimino''>PMID:29478615</ref>.

== Structure ==

~~===Important Structural Features===~~

~~====Active Site====~~

The <scene name='90/904326/Active_site_with_residues/6'>active site</scene> for GTP hydrolysis of Ras is located in the Gap-related domain of neurofibromin. The catalytic residues include R68, Q61, and Y32, as well as magnesium and water molecules. Arginine is referred to as an [http://https://en.wikipedia.org/wiki/Arginine_finger “arginine finger”] because it points into the binding site of GTP to stabilize and orient the position of glutamine through a network of hydrogen bonds between water molecules. This arginine comes from the Gap-related domain of neurofibromin. When GDP is bound, glutamine is too far away to perform its catalytic action. Glutamine interacts with the gamma phosphate via a hydrogen bond created from an interaction between a water molecule and the gamma phosphate. When GTP is bound, tyrosine moves inward to face it. In the GDP bound form, tyrosine faces outward.

====Conformations====

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==== CSRD and CTD ====

The Cysteine-Serine-rich domain (CSRD) and C-terminal domain (CTD) contain phosphorylation sites. The CSRD is able to be phosphorylated by protein kinases A and C. Phosphorylation by protein kinase C is a positive regulator of neurofibromin activity. The CTD is phosphorylated primarily by protein kinase C. This domain is a negative regulator of neurofibromin activity if particular residues are phosphorylated. It also plays an important role in tubulin binding, as it helps in the transition from metaphase to anaphase. CTD contains a nuclear localization signal as well.

===Important Structural Features===

====Active Site====

The <scene name='90/904326/Active_site_with_residues/6'>active site</scene> for GTP hydrolysis of Ras is located in the Gap-related domain of neurofibromin. The catalytic residues include R68, Q61, and Y32, as well as magnesium and water molecules. Arginine is referred to as an [http://https://en.wikipedia.org/wiki/Arginine_finger “arginine finger”] because it points into the binding site of GTP to stabilize and orient the position of glutamine through a network of hydrogen bonds between water molecules. This arginine comes from the Gap-related domain of neurofibromin. When GDP is bound, glutamine is too far away to perform its catalytic action. Glutamine interacts with the gamma phosphate via a hydrogen bond created from an interaction between a water molecule and the gamma phosphate. When GTP is bound, tyrosine moves inward to face it. In the GDP bound form, tyrosine faces outward.

new?

Ras and Neurofibromin associate through an arginine residue, 1276, that comes from neurofibromin. This arginine is referred to as the [http://https://en.wikipedia.org/wiki/Arginine_finger “arginine finger”] and assists in the hydrolysis of GTP by binding to a backbone carbon atom of tyrosine 32 of Ras when neurofibromin is in the open conformation. It points into the GTP binding site of Ras when neurofibromin is in the open conformation. R1276 also helps stabilize the position of Glutamine 61, a key catalytic residue, through hydrogen bonds.

Glutamine 61 of Ras is a residue that facilitates the conversion of GTP to GDP, turning Ras from its active state to inactive state. There is a catalytic water molecule that glutamine interacts with to position the molecule for a nucleophilic attack on the gamma phosphate of GTP. Mutations of this residue have been related to lower rates of hydrolysis. <ref name= ''Frech''>PMID:8136358</ref>. Tyrosine 32 makes water-mediated hydrogen bonds with the gamma phosphate of GTP. This position is also where Ras is phosphorylation to promote the activity of GTPase-activating proteins and GTP hydrolysis. <ref name= ''Bunda''>DOI:10.1038/ncomms9859</ref>

==RAS Complex==

===Mechanism of Ras Coupled with Neurofibromin===

Neurofibromin: Difference between revisions

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@@ Line 3: / Line 3: @@
 Neurofibromin is a cytoplasmic protein located close to the cell membrane that is encoded by the ''NF1'' gene located on chromosome 17 <ref name= ''Bergoug''>PMID:33121128</ref>. It is a suppressor of the [http://https://www.cancer.gov/publications/dictionaries/cancer-terms/def/ras-gene-family Ras] oncogene through its effect on the rate of catalysis from <scene name='90/904325/Ras_full_structure/2'>Ras-GTP</scene> (active) to Ras-GDP (inactive)<ref name= ''Hall''>PMID:12213964</ref>. NF increasing the rate of catalysis of Ras means that Ras spends more time in its inactive state and cannot cause unnecessary cell proliferation linked to cancer<ref name= ''Cimino''>PMID:29478615</ref>.
 == Structure ==
-===Important Structural Features===
-====Active Site====
-The <scene name='90/904326/Active_site_with_residues/6'>active site</scene> for GTP hydrolysis of Ras is located in the Gap-related domain of neurofibromin. The catalytic residues include R68, Q61, and Y32, as well as magnesium and water molecules. Arginine is referred to as an [http://https://en.wikipedia.org/wiki/Arginine_finger “arginine finger”] because it points into the binding site of GTP to stabilize and orient the position of glutamine through a network of hydrogen bonds between water molecules. This arginine comes from the Gap-related domain of neurofibromin. When GDP is bound, glutamine is too far away to perform its catalytic action. Glutamine interacts with the gamma phosphate via a hydrogen bond created from an interaction between a water molecule and the gamma phosphate. When GTP is bound, tyrosine moves inward to face it. In the GDP bound form, tyrosine faces outward.
 ====Conformations====
@@ Line 17: / Line 14: @@
 ==== CSRD and CTD ====
 The Cysteine-Serine-rich domain (CSRD) and C-terminal domain (CTD) contain phosphorylation sites. The CSRD is able to be phosphorylated by protein kinases A and C. Phosphorylation by protein kinase C is a positive regulator of neurofibromin activity. The CTD is phosphorylated primarily by protein kinase C. This domain is a negative regulator of neurofibromin activity if particular residues are phosphorylated. It also plays an important role in tubulin binding, as it helps in the transition from metaphase to anaphase. CTD contains a nuclear localization signal as well.
+===Important Structural Features===
+====Active Site====
+The <scene name='90/904326/Active_site_with_residues/6'>active site</scene> for GTP hydrolysis of Ras is located in the Gap-related domain of neurofibromin. The catalytic residues include R68, Q61, and Y32, as well as magnesium and water molecules. Arginine is referred to as an [http://https://en.wikipedia.org/wiki/Arginine_finger “arginine finger”] because it points into the binding site of GTP to stabilize and orient the position of glutamine through a network of hydrogen bonds between water molecules. This arginine comes from the Gap-related domain of neurofibromin. When GDP is bound, glutamine is too far away to perform its catalytic action. Glutamine interacts with the gamma phosphate via a hydrogen bond created from an interaction between a water molecule and the gamma phosphate. When GTP is bound, tyrosine moves inward to face it. In the GDP bound form, tyrosine faces outward.
+new?
+Ras and Neurofibromin associate through an arginine residue, 1276, that comes from neurofibromin. This arginine is referred to as the [http://https://en.wikipedia.org/wiki/Arginine_finger “arginine finger”] and assists in the hydrolysis of GTP by binding to a backbone carbon atom of tyrosine 32 of Ras when neurofibromin is in the open conformation. It points into the GTP binding site of Ras when neurofibromin is in the open conformation. R1276 also helps stabilize the position of Glutamine 61, a key catalytic residue, through hydrogen bonds.
+Glutamine 61 of Ras is a residue that facilitates the conversion of GTP to GDP, turning Ras from its active state to inactive state. There is a catalytic water molecule that glutamine interacts with to position the molecule for a nucleophilic attack on the gamma phosphate of GTP. Mutations of this residue have been related to lower rates of hydrolysis. <ref name= ''Frech''>PMID:8136358</ref>. Tyrosine 32 makes water-mediated hydrogen bonds with the gamma phosphate of GTP. This position is also where Ras is phosphorylation to promote the activity of GTPase-activating proteins and GTP hydrolysis. <ref name= ''Bunda''>DOI:10.1038/ncomms9859</ref>
 ==RAS Complex==
 ===Mechanism of Ras Coupled with Neurofibromin===