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J Biol Chem, Vol. 273, Issue 24, 15053-15060, June 12, 1998

Mutations at the Domain Interface of G_s Impair Receptor-mediated Activation by Altering Receptor and Guanine Nucleotide Binding

From the Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520-8026

G protein  subunits consist of two domains, a GTPase domain and a helical domain. Receptors activate G proteins by catalyzing replacement of GDP, which is buried between these two domains, with GTP. Substitution of the homologous _i2 residues for four _s residues in switch III, a region that changes conformation upon GTP binding, or of one nearby helical domain residue decreases the ability of _s to be activated by the -adrenergic receptor and by aluminum fluoride. Both sets of mutations increase the affinity of _s for the -adrenergic receptor, based on an increased amount of high affinity binding of the -adrenergic agonist, isoproterenol. The mutations also decrease the rate of receptor-mediated activation and disrupt the ability of the -adrenergic receptor to increase the apparent affinity of _s for the GTP analog, guanosine 5'-O-(3-thiotriphosphate). Simultaneous replacement of the helical domain residue and one of the four switch III residues with the homologous _i2 residues restores normal receptor-mediated activation, suggesting that the defects caused by mutations at the domain interface are due to altered interdomain interactions. These results suggest that interactions between residues across the domain interface are involved in two key steps of receptor-mediated activation, promotion of GTP binding and subsequent receptor-G protein dissociation.

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