Neurofibromin: Difference between revisions

Revision as of 20:12, 26 March 2022

Introduction

Structure

Domains

GRD domain

SEC-PH

CSRD and CTD

Important Structural Features

Active Site

Arginine Finger

The catalytic glutamine is too far away in the GDP bound form to perform any function. The arginine finger stabilizes glutamine which assists the cleaving mechanism.

Conformations

RAS Complex

NF interacts with Ras to form a complex. R68 assists N61 in catalysis.

Mechanism of Ras Coupled with Neurofibromin

The RasGAP interactions that occur when neurofibromin's GAP domain and Ras are bound have two critical catalytic components. The first is the the arginine finger of the NF protein, which stabilizes the catalytic glutamine, as well as stabilizing the transition state of the phosphoryl transfer^[1]. The second component is the catalytic glutamine of the Ras protein, which stabilizes the nucleophilic water as it attacks the third phosphate group in the GTP molecule as shown in Figure 1.

Downstream Effects

Disease Relevance

Mutations to the neurofibromin protein are implicated in the progression of Neurofibromatosis type 1 (NF1). This condition drives several forms of human cancers by inactivating the Ras suppression effects of NF, allowing Ras to behave as an oncogene. Neurofibromatosis type 1 is an autosomal dominant disorder that affects 1 in 3,000 people, and the NF gene itself has the highest mutation rate of any known human gene, adding to its prevalence^[2]. NF1 primarily causes tumors in the central and peripheral nervous systems, but often has a multisystem expression including tumors in the dermatologic, cardiovascular, gastrointestinal, and orthopedic systems^[3]. The wide range of presentations is consistent with the multiplicity of mutations observed in the causative protein^[4]. This is a sample scene created with SAT to color by Group, and another to make a transparent representation of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

↑ Scheffzek K, Shivalingaiah G. Ras-Specific GTPase-Activating Proteins-Structures, Mechanisms, and Interactions. Cold Spring Harb Perspect Med. 2019 Mar 1;9(3). pii: cshperspect.a031500. doi:, 10.1101/cshperspect.a031500. PMID:30104198 doi:https://dx.doi.org/10.1101/cshperspect.a031500
↑ Lupton CJ, Bayly-Jones C, D'Andrea L, Huang C, Schittenhelm RB, Venugopal H, Whisstock JC, Halls ML, Ellisdon AM. The cryo-EM structure of the human neurofibromin dimer reveals the molecular basis for neurofibromatosis type 1. Nat Struct Mol Biol. 2021 Dec;28(12):982-988. doi: 10.1038/s41594-021-00687-2., Epub 2021 Dec 9. PMID:34887559 doi:https://dx.doi.org/10.1038/s41594-021-00687-2
↑ Cimino PJ, Gutmann DH. Neurofibromatosis type 1. Handb Clin Neurol. 2018;148:799-811. doi: 10.1016/B978-0-444-64076-5.00051-X. PMID:29478615 doi:https://dx.doi.org/10.1016/B978-0-444-64076-5.00051-X
↑ Ly KI, Blakeley JO. The Diagnosis and Management of Neurofibromatosis Type 1. Med Clin North Am. 2019 Nov;103(6):1035-1054. doi: 10.1016/j.mcna.2019.07.004. PMID:31582003 doi:https://dx.doi.org/10.1016/j.mcna.2019.07.004

References

Proteopedia Page Contributors and Editors (what is this?)

Jordyn K. Lenard, Ryan D. Adkins, OCA, Michal Harel, Jaime Prilusky

[0-1] Scheffzek K, Shivalingaiah G. Ras-Specific GTPase-Activating Proteins-Structures, Mechanisms, and Interactions. Cold Spring Harb Perspect Med. 2019 Mar 1;9(3). pii: cshperspect.a031500. doi:, 10.1101/cshperspect.a031500. PMID:30104198 doi:https://dx.doi.org/10.1101/cshperspect.a031500

[1-2] Lupton CJ, Bayly-Jones C, D'Andrea L, Huang C, Schittenhelm RB, Venugopal H, Whisstock JC, Halls ML, Ellisdon AM. The cryo-EM structure of the human neurofibromin dimer reveals the molecular basis for neurofibromatosis type 1. Nat Struct Mol Biol. 2021 Dec;28(12):982-988. doi: 10.1038/s41594-021-00687-2., Epub 2021 Dec 9. PMID:34887559 doi:https://dx.doi.org/10.1038/s41594-021-00687-2

[2-3] Cimino PJ, Gutmann DH. Neurofibromatosis type 1. Handb Clin Neurol. 2018;148:799-811. doi: 10.1016/B978-0-444-64076-5.00051-X. PMID:29478615 doi:https://dx.doi.org/10.1016/B978-0-444-64076-5.00051-X

[3-4] Ly KI, Blakeley JO. The Diagnosis and Management of Neurofibromatosis Type 1. Med Clin North Am. 2019 Nov;103(6):1035-1054. doi: 10.1016/j.mcna.2019.07.004. PMID:31582003 doi:https://dx.doi.org/10.1016/j.mcna.2019.07.004

[1]

@@ Line 17: / Line 17: @@
 <scene name='90/904325/Ras_nf1_complex/2'>NF interacts with Ras to form a complex. R68 assists N61 in catalysis.</scene>
 ===Mechanism of Ras Coupled with Neurofibromin===
-The RasGAP interactions that occur when neurofibromin's GAP domain and Ras are bound have two critical catalytic components. The first is the arginine finger
+The RasGAP interactions that occur when neurofibromin's GAP domain and Ras are bound have two critical catalytic components. The first is the <scene name='90/904325/Arginine_finger_and_gtp/1'>the arginine finger</scene> of the NF protein, which stabilizes the catalytic glutamine, as well as stabilizing the transition state of the phosphoryl transfer<ref name= ''Scheffzek''>PMID:30104198</ref>. The second component is the catalytic glutamine of the Ras protein, which stabilizes the nucleophilic water as it attacks the third phosphate group in the GTP molecule as shown in Figure 1.
-[[Image:Ras mechanism.jpg|400 px|right|thumb|Figure X]]
+[[Image:Ras mechanism.jpg|400 px|right|thumb|Figure 1: The catalytic glutamine stabilizes the nucleophilic water.]]
 ===Downstream Effects===
 [[Image:Signal_transduction_pathways.png|400 px|right|thumb|Figure X; By cybertory - This file was derived from: Signal transduction v1.png, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=12081090]]