RAS GAP proteins interact with RAS by inserting an arginine ...

created [InstanceEdit:9658309] Rothfels, Karen, 2019-08-12
dbId 9658308
displayName RAS GAP proteins interact with RAS by inserting an arginine ...
schemaClass Summation
text 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).
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