<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>
===Mechanism of Ras Coupled with Neurofibromin===
===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 <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.
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<ref name= ''Prive''>PMID:1565661</ref>.
[[Image:Ras mechanism.jpg|400 px|right|thumb|Figure 1: The catalytic glutamine stabilizes the nucleophilic water.]]
[[Image:Ras mechanism.jpg|400 px|right|thumb|Figure 1: The catalytic glutamine stabilizes the nucleophilic water.]]
Neurofibromin is a cytoplasmic protein located close to the cell membrane that is encoded by the NF1 gene located on chromosome 17 [1]. It is a suppressor of the Ras oncogene through its effect on the rate of catalysis from Ras-GTP (active) to Ras-GDP (inactive)[2]. 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[3].
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[4]. 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[5].
Figure 1: The catalytic glutamine stabilizes the nucleophilic water.
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[6]. 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[7]. The wide range of presentations is consistent with the multiplicity of mutations observed in the causative protein[8].
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.
↑Bergoug M, Doudeau M, Godin F, Mosrin C, Vallee B, Benedetti H. Neurofibromin Structure, Functions and Regulation. Cells. 2020 Oct 27;9(11). pii: cells9112365. doi: 10.3390/cells9112365. PMID:33121128 doi:https://dx.doi.org/10.3390/cells9112365
↑Hall BE, Bar-Sagi D, Nassar N. The structural basis for the transition from Ras-GTP to Ras-GDP. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12138-42. Epub 2002 Sep 4. PMID:12213964 doi:https://dx.doi.org/10.1073/pnas.192453199
↑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
↑Prive GG, Milburn MV, Tong L, de Vos AM, Yamaizumi Z, Nishimura S, Kim SH. X-ray crystal structures of transforming p21 ras mutants suggest a transition-state stabilization mechanism for GTP hydrolysis. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3649-53. doi: 10.1073/pnas.89.8.3649. PMID:1565661 doi:https://dx.doi.org/10.1073/pnas.89.8.3649
↑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
↑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
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