Hydrolysis of GTP by the α‐chain of G s and other GTP binding proteins

The functions of G proteins—like those of bacterial elongation factor (EF) Tu and the 21 kDa ras proteins (p21 ras )—depend upon their abilities to bind and hydrolyze GTP and to assume different conformations in GTP‐ and GDP‐bound states. Similarities in function and amino acid sequence indicate that EF‐Tu, p21 ras , and G protein α‐chains evolved from a primordial GTP‐binding protein. Proteins in all three families appear to share common mechanisms for GTP‐dependent conformational change and hydrolysis of bound GTP. Biochemical and molecular genetic studies of the α‐chain of G s (α s ) point to key regions that are involved in GTP‐dependent conformational change and in hydrolysis of GTP. Tumorigenic mutations of α s in human pituitary tumors inhibit‐the protein's GTPase activity and cause constitutive elevation of adenylyl cyclase activity. One such mutation replaces a Gln residue in α s that corresponds to Gln‐61 of p21 ras ; mutational replacements of this residue in both proteins inhibit their GTPase activities. A second class of the GTPase inhibiting mutations in α s occurs in the codon for an ARG residue whose covalent modification by cholera toxin also inhibits GTP hydrolysis by α s . This Arg residue is located in a domain of α s not represented in EF‐Tu or p21 ras . We propose that this domain constitutes an intrinsic activator of GTP hydrolysis, and that it performs a function analogous to that performed for EF‐Tu by the programmed ribosome and for p21 ras by the recently discovered GTPase‐activating protein. Owing to their inherited similarities of structure and function, what we learn about α s , p21 ras , or EF‐tu as individual molecules helps us to understand crucial functions of other members of the super‐family.