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Originally published In Press as doi:10.1074/jbc.M208787200 on November 8, 2002

J. Biol. Chem., Vol. 278, Issue 8, 6050-6058, February 21, 2003
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G Protein-coupled Receptor Kinase 2/Galpha q/11 Interaction
A NOVEL SURFACE ON A REGULATOR OF G PROTEIN SIGNALING HOMOLOGY DOMAIN FOR BINDING Galpha SUBUNITS*

Rachel Sterne-MarrDagger §, John J. G. Tesmer, Peter W. Day||, RoseAnn P. StracquatanioDagger ||, Jill-Ann E. CilenteDagger , Katharine E. O'ConnorDagger , Alexey N. Pronin||**, Jeffrey L. Benovic||, and Philip B. Wedegaertner||

From the Dagger  Biology Department, Siena College, Loudonville, New York 12211, the  Department of Chemistry and Biochemistry, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, the || Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and ** Senomyx, Inc., La Jolla, California 92037

G protein-coupled receptors (GPCRs) transduce cellular signals from hormones, neurotransmitters, light, and odorants by activating heterotrimeric guanine nucleotide-binding (G) proteins. For many GPCRs, short term regulation is initiated by agonist-dependent phosphorylation by GPCR kinases (GRKs), such as GRK2, resulting in G protein/receptor uncoupling. GRK2 also regulates signaling by binding Galpha q/ll and inhibiting Galpha q stimulation of the effector phospholipase Cbeta . The binding site for Galpha q/ll resides within the amino-terminal domain of GRK2, which is homologous to the regulator of G protein signaling (RGS) family of proteins. To map the Galpha q/ll binding site on GRK2, we carried out site-directed mutagenesis of the RGS homology (RH) domain and identified eight residues, which when mutated, alter binding to Galpha q/ll. These mutations do not alter the ability of full-length GRK2 to phosphorylate rhodopsin, an activity that also requires the amino-terminal domain. Mutations causing Galpha q/ll binding defects impair recruitment to the plasma membrane by activated Galpha q and regulation of Galpha q-stimulated phospholipase Cbeta activity when introduced into full-length GRK2. Two different protein interaction sites have previously been identified on RH domains. The Galpha binding sites on RGS4 and RGS9, called the "A" site, is localized to the loops between helices alpha 3 and alpha 4, alpha 5 and alpha 6, and alpha 7 and alpha 8. The adenomatous polyposis coli (APC) binding site of axin involves residues on alpha  helices 3, 4, and 5 (the "B" site) of its RH domain. We demonstrate that the Galpha q/ll binding site on the GRK2 RH domain is distinct from the "A" and "B" sites and maps primarily to the COOH terminus of its alpha 5 helix. We suggest that this novel protein interaction site on an RH domain be designated the "C" site.

* This work was supported by National Science Foundation Grant MCB9728179 and an American Heart Association Southeastern Pennsylvania Affiliate Beginning grant-in-aid (to R. S. M.), American Heart Association Texas Affiliate Beginning Grant-in-aid 0060118Y and a Welch Foundation Chemical Research Grant F-1487 (to J. J. G. T.), a fellowship from the American Heart Association Pennsylvania-Delaware Affiliate (to P. W. D.), National Institutes of Health Grants GM44944 and GM47417 (to J. L. B.) and GM56444 and GM628884, and a grant from the Pew Scholars Program in the Biomedical Sciences (to P. B. W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Siena College, Biology Dept., 123 Morrell Science Center, 515 Loudon Rd., Loudonville, NY 12211. Tel.: 518-783-2462; Fax: 518-783-2986; E-mail: sternemarr@siena.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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