G protein selectivity is a determinant of RGS2 function

RGS (regulator of G protein signaling) proteins are GTPase-activating prote ins that attenuate signaling by heterotrimeric G proteins. Whether the biol ogical functions of RGS proteins are governed by quantitative differences i n GTPase-activating protein activity toward various classes of G alpha subu nits and how G protein selectivity is achieved by differences in RGS protei n structure are largely unknown. Here we provide evidence indicating that t he function of RGS2 is determined in part by differences in potency toward G(q) versus G(i) family members. RGS2 was 5-fold more potent than RGS4 as a n inhibitor of G(q)-stimulated phosphoinositide hydrolysis in vivo. In cont rast, RGS4 was 8-fold more potent than RGS2 as an inhibitor of G(i)-mediate d signaling. RGS2 mutants were identified that display increased potency to ward G(i) family members without affecting potency toward G(q). These mutat ions and the structure of RGS4-G(i)alpha(1) complexes suggest that RGS2-G(i )alpha interaction is unfavorable in part because of the geometry of the sw itch I binding pocket of RGS2 and a potential interaction between the alpha 8-alpha 9 loop of RGS2 and alpha A of G(i) class alpha subunits. The resul ts suggest that the function of RGS2 relative to other RGS family members i s governed in part by quantitative differences in activity toward different classes of G alpha subunits.