The Ras-RasGAP Complex: How to Complement an Inefficient Active Site

Abstract

GTP-hydrolysis as carried out by GTP-binding proteins^[1] is intrinsically very slow but can be accelerated by orders of magnitude upon interaction with GTPase Activating Proteins, GAPs, which are specific for the respective GTP-binding proteins. Focusing on p21ras (Ras), a key element in growth control and differentiation, we have used biochemical and structural methods to elucidate the mechanism of GTPase activation. An arginine side chain is supplied into the active site of Ras to contact the nucleotide and stabilize the transition state of the reaction, consistent with mutational analyses. The switch II region of Ras is stabilized by GAP-334 to allow Gln61, the mutation of which activates the oncogenic potential of Ras, to participate in catalysis. The structure provides an explanation how Gly12 and Gln61 mutations might escape regulation by GAPs.