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 Ras oncogene through its effect on the rate of catalysis from Ras-GTP (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>.  
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 Ras oncogene through its effect on the rate of catalysis from Ras-GTP (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 ==
== 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 “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.
====Arginine Finger====
<scene name='90/904325/Arginine_finger_and_gdp/2'>The catalytic glutamine is too far away from the GDP substrate for any interaction to occur.</scene>
<scene name='90/904325/Arginine_finger_and_gtp/2'>The arginine finger stabilizes the catalytic glutamine, assisting in cleavage of the 3rd phosphate group.</scene>
====Conformations====
Neurofibromin is a dimeric protein that is found in the cytoplasm. It exists in two conformations, <scene name='90/904326/Open_conformation/2'>open</scene> and <scene name='90/904326/Closed_conformation/2'>closed</scene> . The open conformation has one of the protomers in an auto-inhibited conformation and the other in an open conformation. In the <scene name='90/904326/Open_conformation_with_grd_hig/2'>open conformation</scene>, Ras is able to bind to the GRD neurofibromin. The <scene name='90/904326/Grd_closed_conformation/2'>closed conformation</scene> has both protomers in an autoinhibited conformation, which sterically hinders the binding of Ras to GRD.
===Domains===
===Domains===
[[Image:Csrd,grd,sec,ctd.png]]
[[Image:Csrd,grd,sec,ctd.png]]
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==== CSRD and CTD ====
==== 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.  
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 “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.
====Arginine Finger====
<scene name='90/904325/Arginine_finger_and_gdp/2'>The catalytic glutamine is too far away from the GDP substrate for any interaction to occur.</scene>
<scene name='90/904325/Arginine_finger_and_gtp/2'>The arginine finger stabilizes the catalytic glutamine, assisting in cleavage of the 3rd phosphate group.</scene>
====Conformations====
Neurofibromin is a dimeric protein that is found in the cytoplasm. It exists in two conformations, <scene name='90/904326/Open_conformation/2'>open</scene> and <scene name='90/904326/Closed_conformation/2'>closed</scene> . The open conformation has one of the protomers in an auto-inhibited conformation and the other in an open conformation. In the <scene name='90/904326/Open_conformation_with_grd_hig/2'>open conformation</scene>, Ras is able to bind to the GRD neurofibromin. The <scene name='90/904326/Grd_closed_conformation/2'>closed conformation</scene> has both protomers in an autoinhibited conformation, which sterically hinders the binding of Ras to GRD.
==RAS Complex==  
==RAS Complex==  
<scene name='90/904325/Ras_nf1_complex/2'>NF interacts with Ras to form a complex. R68 assists N61 in catalysis.</scene>
<scene name='90/904325/Ras_nf1_complex/2'>NF interacts with Ras to form a complex. R68 assists N61 in catalysis.</scene>
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