Structural insights into g-protein signalling

The a subunits of heterotrimeric G proteins act both as direct and indirect regulators of effectors in heptahelical receptor-stimulated signal transduction pathways. G protein a subunits are themselves subject to the action of Regulators of G protein Signalling (RGS proteins).Crystallographic studies of Giol and its protein complexes demonstrate that the switch II region of c discriminates among alternative interaction partners in a nucleotide-dependent fashion. The GTP-bound form of Giol, for example, binds to and negatively regulates several isoforms of adenylyl cyclase. GTP directly stabilizes the switch II and switch lII regions of Giol which participate in effector binding; in contrast, these segments are highly flexible in the GDP-bound state. The latter form of Gi1 recognizes G-protein β7 heterodimers. The crystal structure of the heterotrimeric complex demonstrates that, in order to form part of the β7 recognition surface, switch II must adopt an ordered conformation that is distinct from that observed ia the GTP complex, and cannot bind GTP. The rate at which Gic,1 catalyzes the hydrolysis of GTP is increased fifty-fold by RGS4. RGS4 binds directly to the three switch regions of Gial and is complementary to the transition state complex of the a subunit. A welt conserved asparagine residue may act catalyticallyI and mutation to serine reduces the GTPase activating ability of RGS4. Naturally occurlng RGS proteins with serine at this position may act in part as effector competitors.