title: Structural and functional analysis of the regulator of G protein signaling 2-gαq complex.
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.
authors: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109-2216, USA.
authors: Mark R
authors: MR
authors: Nance
authors: Barry
authors: B
authors: Kreutz
authors: Valerie M
authors: VM
authors: Tesmer
authors: Rachel
authors: R
authors: Sterne-Marr
authors: Tohru
authors: T
authors: Kozasa
authors: John J G
authors: JJ
authors: Tesmer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry* / Q000235:genetics; D020710:RGS Proteins / Q000737:chemistry* / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D021122:Protein Subunits; D020710:RGS Proteins; C087182:RGS2 protein, human; D011994:Recombinant Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11