Journal article
High-resolution structure of RGS17 suggests a role for Ca2+ in promoting the GTPase-activating protein activity by RZ subfamily members
The Journal of biological chemistry, Vol.294(20), pp.8148-8160
05/2019
DOI: 10.1074/jbc.RA118.006059
PMCID: PMC6527179
PMID: 30940727
Abstract
Regulator 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 Gα subunits. Members of the RZ subfamily of RGS proteins bind to activated Gαo, Gαz, and Gαi1–3 proteins in the nervous system and thereby inhibit downstream pathways, including those involved in Ca2+-dependent signaling. In contrast to other RGS proteins, little is known about RZ subfamily structure and regulation. Herein, we present the 1.5-Å crystal structure of RGS17, the most complete and highest-resolution structure of an RZ subfamily member to date. RGS17 cocrystallized with Ca2+ bound to conserved positions on the predicted Gα-binding surface of the protein. Using NMR chemical shift perturbations, we confirmed that Ca2+ binds in solution to the same site. Furthermore, RGS17 had greater than 55-fold higher affinity for Ca2+ than for Mg2+. Finally, we found that Ca2+ promotes interactions between RGS17 and activated Gα and decreases the Km for GTP hydrolysis, potentially by altering the binding mechanism between these proteins. Taken together, these findings suggest that Ca2+ positively regulates RGS17, which may represent a general mechanism by which increased Ca2+ concentration promotes the GAP activity of the RZ subfamily, leading to RZ-mediated inhibition of Ca2+ signaling.
Details
- Title: Subtitle
- High-resolution structure of RGS17 suggests a role for Ca2+ in promoting the GTPase-activating protein activity by RZ subfamily members
- Creators
- Monita Sieng - Department of Chemistry, Purdue University, West Lafayette, Indiana 47907Michael P Hayes - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242Joseph B O’Brien - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242C. Andrew Fowler - NMR Facility, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242Jon C Houtman - Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa 52242David L Roman - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242Angeline M Lyon - Department of Chemistry, Purdue University, West Lafayette, Indiana 47907
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.294(20), pp.8148-8160
- DOI
- 10.1074/jbc.RA118.006059
- PMID
- 30940727
- PMCID
- PMC6527179
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Grant note
- 2T32GM008365-26A / National Institutes of Health Training IRG-14-190-56 / American Cancer Society 16SDG29920017 / American Heart Association Scientist
- Language
- English
- Date published
- 05/2019
- Academic Unit
- Pharmacy; Microbiology and Immunology; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry; Internal Medicine
- Record Identifier
- 9984065491702771
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