1. Structural and Functional Analysis of the Regulator of G Protein Signaling 2-Gαq Complex
- Author
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Tohru Kozasa, Mark R. Nance, Valerie M. Tesmer, Barry Kreutz, John J.G. Tesmer, and Rachel Sterne-Marr
- Subjects
GTPase-activating protein ,GTP-Binding Protein alpha Subunits ,Molecular Sequence Data ,Biology ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,Protein Structure, Secondary ,Mice ,Structure-Activity Relationship ,Protein structure ,Regulator of G protein signaling ,Structural Biology ,Heterotrimeric G protein ,Escherichia coli ,Animals ,Humans ,Protein Interaction Domains and Motifs ,Amino Acid Sequence ,Molecular Biology ,RGS2 ,Binding Sites ,Recombinant Proteins ,Cell biology ,Rats ,Molecular Docking Simulation ,G beta-gamma complex ,Protein Subunits ,Biochemistry ,Mutation ,GTP-Binding Protein alpha Subunits, Gq-G11 ,Cattle ,RGS Proteins ,Sequence Alignment ,Protein Binding - Abstract
The 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.
- Published
- 2013
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