RGS10 is a selective activator of Gα_i GTPase activity

Abstract

POLYPEPTIDES that define a protein family termed RGS (for regulators of G-protein signalling) are encoded by the SST2 gene of the yeast Saccharomyces cerevisiae, the EGL-10 gene of the nematode Caenorhabdatis elegans, and several related mammalian genes. Genetic studies in invertebrates and mammalian cell-transfection experiments indicate that RGS proteins negatively regulate signalling pathways involving seven transmem-brane receptors and heterotrimeric G proteins^1–3. However, the biochemical mechanism by which RGS proteins control these pathways is unknown. Here we report the characterization of human RGS10, a member of this protein family. Co-immunopre-cipitation studies demonstrate that RGS10 associates specifically with the activated forms of two related G-protein subunits, Gα_i3 and Gα _z, but fails to interact with the structurally and functionally distinct Gα _s subunit. In vitro assays with purified proteins indicate that RGS10 increases potently and selectively the GTP hydrolytic activity of several members of the Gα _i family, including Gα _i3, Gα _z and Gα _o. These results demonstrate that RGS proteins can attenuate signalling pathways involving heterotrimeric G proteins by serving as GTPase-activating proteins for specific types of Gα subunits.