RAS proteins cycle between an active GTP-bound state and an inactive GDP-bound state. GTPase activating proteins (GAPs) stimulate the low intrinsic GTPase activity of RAS proteins, converting the active to the inactive form, while guanine nucleotide exchange factors (GEFs) stimulate the intrinsic dissociation of GDP, allowing its replacement with GTP and consequent activation of RAS.
Disease-causing mutations in RAS promote constitutive signaling by favouring the accumulation of RAS:GTP. The vast majority of these mutations are loss of function mutations at G12, G13 and Q61. These mutations disrupt the GTPase activity of RAS proteins by interfering with nucleophilic attack on the gamma phosphate of GTP. A smaller proportion of RAS mutations increase the intrinsic GDP dissociation rate, while other mutations interfere with RAS interactions with GAPs (reviewed in Prior et al, 2012; Pylayeva-Gupta et al, 2011; Stephen et al, 2014; Samatar and Poulikakos, 2014).