Structural and Functional Analysis of the Regulator of G Protein Signaling 2-Gαq Complex

The heterotrimeric G protein G alpha(q) is a key regulator of blood pressure, and excess G alpha(q) signaling leads to hypertension. A specific inhibitor of G alpha(q) is the GTPase activating protein (GAP) known as regulator of G protein signaling 2 (RGS2). The molecular basis for how G alpha(q/11) subunits serve as substrates for RGS proteins and how RGS2 mandates its selectivity for G alpha(q) is poorly understood. In crystal structures of the RGS2-G alpha(q) complex, RGS2 docks to G alpha(q) in a different orientation from that observed in RGS-G alpha(i/o) complexes. Despite its unique pose, RGS2 maintains canonical interactions with the switch regions of G alpha(q) in part because its alpha 6 helix adopts a distinct conformation. We show that RGS2 forms extensive interactions with the alpha-helical domain of G alpha(q) that contribute to binding affinity and GAP potency. RGS subfamilies that do not serve as GAPs for G alpha(q) are unlikely to form analogous stabilizing interactions.