SUBSTRATE-ASSISTED CATALYSIS AS A MECHANISM FOR GTP HYDROLYSIS OF P21(RAS) AND OTHER GTP-BINDING PROTEINS

Despite many advances in understanding the structure and function of G TP-binding proteins the mechanism by which these molecules switch from the GTP-bound on-state to the GDP-bound off-state is still poorly und erstood. Theoretical studies suggest that the activation of the nucleo philic water which hydrolyzes GTP needs a general base. Such a base co uld not be located in any of the many GTP-binding proteins. Here we pr esent a unique type of linear free energy relationships that not only supports a mechanism for p21(ras) in which the substrate GTP itself ac ts as the catalytic base driving the GTPase reaction but can also help to explain why certain mutants of p21(ras) are oncogenic and others a re not.