RAS GAP mutants aren't stimulated by GAPs

Stable Identifier
Reaction [transition]
Homo sapiens
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RAS GAP proteins interact with RAS by inserting an arginine finger into the RAS active site to promote positioning of the catalytic Q61 residue, stimulating the low intrinsic GTPase activity by several orders of magnitude (Ahmadian et al, 2003; Ahmadian et al, 1997; reviewed in Bos et al, 2007). Many of the common mutations in RAS proteins found in cancer interfere with the ability of RAS GAPs to stimulate the intrinsic GTPase of the proteins. Mutation of the catalytic Q61 disrupts coordination of a water molecule that is required for nucleophilic attack on the gamma phosphate of GTP, while G12 and G13 mutations abrogate interactions with RAS GAP proteins that are required for proper positioning of the Q61 residue (Trahey et al, 1987; Scheidig et al, 1999; Buhrman et al, 2010; Scheffzek et al,1997).
In addition to somatic mutations in cancer, RAS is also subject to germline mutations that lead to a group of developmental disorders collectively known as RASopathies (reviewed in Rauen, 2013; Tidyman and Rauen, 2009). Like their oncogenic counterparts, these RAS mutants show defective GTP hydrolysis and constitutive signaling (Schubbert et al, 2006; Schubbert et al, 2007).

Literature References
PubMed ID Title Journal Year
19467855 The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation

Tidyman, WE, Rauen, KA

Curr. Opin. Genet. Dev. 2009
20194776 Allosteric modulation of Ras positions Q61 for a direct role in catalysis

Fetics, S, Holzapfel, G, Mattos, C, Buhrman, G

Proc. Natl. Acad. Sci. U.S.A. 2010
16474405 Germline KRAS mutations cause Noonan syndrome

Kalscheuer, V, Niemeyer, CM, Nguyen, H, Zenker, M, Zhang, KY, Wehner, LE, Klein, C, West, B, Shannon, K, Rauch, A, Schubbert, S, Kratz, CP, van der Burgt, I, Bollag, G, Rowe, SL, Sistermans, E, Musante, L, Böll, S

Nat. Genet. 2006
17540168 GEFs and GAPs: critical elements in the control of small G proteins

Wittinghofer, A, Rehmann, H, Bos, JL

Cell 2007
10574788 The pre-hydrolysis state of p21(ras) in complex with GTP: new insights into the role of water molecules in the GTP hydrolysis reaction of ras-like proteins

Goody, RS, Scheidig, AJ, Burmester, C

Structure 1999
17875937 Biochemical and functional characterization of germ line KRAS mutations

Niemeyer, CM, Shannon, K, Nguyen, H, Zenker, M, Lyubynska, N, Schubbert, S, Kratz, CP, Molven, A, Bollag, G

Mol. Cell. Biol. 2007
12787671 Structural fingerprints of the Ras-GTPase activating proteins neurofibromin and p120GAP

Scheffzek, K, Ahmadian, MR, Stege, P, Kiel, C

J. Mol. Biol. 2003
2821624 A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants

McCormick, F, Trahey, M

Science 1987
9302992 Confirmation of the arginine-finger hypothesis for the GAP-stimulated GTP-hydrolysis reaction of Ras

Scheffzek, K, Ahmadian, MR, Wittinghofer, A, Stege, P

Nat. Struct. Biol. 1997
23875798 The RASopathies

Rauen, KA

Annu Rev Genomics Hum Genet 2013
9219684 The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants

Lautwein, A, Ahmadian, MR, Schmitz, F, Kabsch, W, Wittinghofer, A, Wiesmuller, L, Scheffzek, K

Science 1997
Normal reaction
Functional status

Loss of function of RAS GAP mutants:GTP [plasma membrane]

Name Identifier Synonyms
cardiofaciocutaneous syndrome DOID:0060233 CFC syndrome, cardio-facial-cutaneous syndrome
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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