6am3
Regulator of G protein signaling (RGS) 17 in complex with Ca2+
Structural highlights
FunctionRGS17_HUMAN Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits thereby driving them into their inactive GDP-bound form. Binds selectively to G(z)-alpha and G(alpha)-i2 subunits, accelerates their GTPase activity and regulates their signaling activities. The G(z)-alpha activity is inhibited by the phosphorylation and palmitoylation of the G-protein. Negatively regulates mu-opioid receptor-mediated activation of the G-proteins (By similarity). Publication Abstract from PubMedRegulator of G protein signaling (RGS) proteins are negative regulators of G protein-coupled receptor (GPCR) signaling through their ability to act as GTPase-activating proteins (GAPs) for activated Galpha subunits. Members of the RZ subfamily of RGS proteins bind to activated Galphao, Galphaz, and Galphai1-3 proteins in the nervous system and thereby inhibit downstream pathways, including those involved in Ca(2+)-dependent signaling. In contrast to other RGS proteins, little is known about RZ subfamily structure and regulation. Herein, we present the 1.5-A crystal structure of RGS17, the most complete and highest-resolution structure of an RZ subfamily member to date. RGS17 cocrystallized with Ca(2+) bound to conserved positions on the predicted Galpha-binding surface of the protein. Using NMR chemical shift perturbations, we confirmed that Ca(2+) binds in solution to the same site. Furthermore, RGS17 had greater than 55-fold higher affinity for Ca(2+) than for Mg(2+) Finally, we found that Ca(2+) promotes interactions between RGS17 and activated Galpha and decreases the Km for GTP hydrolysis, potentially by altering the binding mechanism between these proteins. Taken together, these findings suggest that Ca(2+) positively regulates RGS17, which may represent a general mechanism by which increased Ca(2+) concentration promotes the GAP activity of the RZ subfamily, leading to RZ-mediated inhibition of Ca(2+) signaling. High-resolution structure of RGS17 suggests a role for Ca(2+) in promoting the GTPase-activating protein activity by RZ subfamily members.,Sieng M, Hayes MP, O'Brien JB, Andrew Fowler C, Houtman JC, Roman DL, Lyon AM J Biol Chem. 2019 May 17;294(20):8148-8160. doi: 10.1074/jbc.RA118.006059. Epub, 2019 Apr 2. PMID:30940727[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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