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

SummaryThe heterotrimeric G protein Gαq is a key regulator of blood pressure, and excess Gαq signaling leads to hypertension. A specific inhibitor of Gαq is the GTPase activating protein (GAP) known as regulator of G protein signaling 2 (RGS2). The molecular basis for how Gαq/11 subunits serve as substrates for RGS proteins and how RGS2 mandates its selectivity for Gαq is poorly understood. In crystal structures of the RGS2-Gαq complex, RGS2 docks to Gαq in a different orientation from that observed in RGS-Gαi/o complexes. Despite its unique pose, RGS2 maintains canonical interactions with the switch regions of Gαq in part because its α6 helix adopts a distinct conformation. We show that RGS2 forms extensive interactions with the α-helical domain of Gαq that contribute to binding affinity and GAP potency. RGS subfamilies that do not serve as GAPs for Gαq are unlikely to form analogous stabilizing interactions.

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► Two structures of the RGS2-Gαq complex were determined by X-ray crystallography
► RGS2 binds Gαq in a manner distinct from how other RGS proteins bind Gαi/o
► In its distinct pose, RGS2 forms extensive contacts with the α-helical domain of Gαq
► Helical domain contacts contribute to binding affinity and GAP potency of RGS2