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Science 300 (5623): 1256-1262

Copyright © 2003 by the American Association for the Advancement of Science

Keeping G Proteins at Bay: A Complex Between G Protein-Coupled Receptor Kinase 2 and Gß{gamma}

David T. Lodowski,1 Julie A. Pitcher,2 W. Darrell Capel,3 Robert J. Lefkowitz,3 John J. G. Tesmer1*

Abstract: The phosphorylation of heptahelical receptors by heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptor kinases (GRKs) is a universal regulatory mechanism that leads to desensitization of G protein signaling and to the activation of alternative signaling pathways.We determined the crystallographic structure of bovine GRK2 in complex with G protein ß1{gamma}2 subunits.Our results show how the three domains of GRK2–the RGS (regulator of G protein signaling) homology, protein kinase, and pleckstrin homology domains–integrate their respective activities and recruit the enzyme to the cell membrane in an orientation that not only facilitates receptor phosphorylation, but also allows for the simultaneous inhibition of signaling by G{alpha} and Gß{gamma} subunits.

1 Institute for Cellular and Molecular Biology, Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA.
2 MRC Laboratory for Molecular and Cell Biology and Cell Biology Unit, Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
3 Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.

* To whom correspondence should be addressed. E-mail: tesmer{at}mail.utexas.edu


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A. Dinudom, A. B. Fotia, R. J. Lefkowitz, J. A. Young, S. Kumar, and D. I. Cook (2004)
PNAS 101, 11886-11890
   Abstract »    Full Text »    PDF »
Coordination of Membrane Excitability through a GIRK1 Signaling Complex in the Atria.
E. N. Nikolov and T. T. Ivanova-Nikolova (2004)
J. Biol. Chem. 279, 23630-23636
   Abstract »    Full Text »    PDF »
Imaging of Muscarinic Acetylcholine Receptor Signaling in Hippocampal Neurons: Evidence for Phosphorylation-Dependent and -Independent Regulation by G-Protein-Coupled Receptor Kinases.
J. M. Willets, M. S. Nash, R. A. J. Challiss, and S. R. Nahorski (2004)
J. Neurosci. 24, 4157-4162
   Abstract »    Full Text »    PDF »
G Protein-coupled Receptor Kinase 2 Regulator of G Protein Signaling Homology Domain Binds to Both Metabotropic Glutamate Receptor 1a and G{alpha}q to Attenuate Signaling.
G. K. Dhami, L. B. Dale, P. H. Anborgh, K. E. O'Connor-Halligan, R. Sterne-Marr, and S. S. G. Ferguson (2004)
J. Biol. Chem. 279, 16614-16620
   Abstract »    Full Text »    PDF »
Conservation and covariance in PH domain sequences: physicochemical profile and information theoretical analysis of XLA-causing mutations in the Btk PH domain.
B. Shen and M. Vihinen (2004)
Protein Eng. Des. Sel. 17, 267-276
   Abstract »    Full Text »    PDF »
G Protein Signaling: Insights from New Structures.
A. M. Preininger and H. E. Hamm (2004)
Sci. STKE 2004, re3
   Abstract »    Full Text »    PDF »
KinG: a database of protein kinases in genomes.
A. Krupa, K. R. Abhinandan, and N. Srinivasan (2004)
Nucleic Acids Res. 32, D153-155
   Abstract »    Full Text »    PDF »
Development of a Yeast Bioassay to Characterize G Protein-coupled Receptor Kinases: IDENTIFICATION OF AN NH2-TERMINAL REGION ESSENTIAL FOR RECEPTOR PHOSPHORYLATION.
B. Noble, L. A. Kallal, M. H. Pausch, and J. L. Benovic (2003)
J. Biol. Chem. 278, 47466-47476
   Abstract »    Full Text »    PDF »
Organization and Functions of Interacting Domains for Signaling by Protein-Protein Interactions.
E. Buck and R. Iyengar (2003)
Sci. STKE 2003, re14
   Abstract »    Full Text »    PDF »
Probing the Roles of Protein Kinases in G-Protein-Coupled Receptor Desensitization.
R. B. Clark and T. C. Rich (2003)
Mol. Pharmacol. 64, 1015-1017
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Targeting G{beta}{gamma} Signaling to Inhibit Prostate Tumor Formation and Growth.
A. L. Bookout, A. E. Finney, R. Guo, K. Peppel, W. J. Koch, and Y. Daaka (2003)
J. Biol. Chem. 278, 37569-37573
   Abstract »    Full Text »    PDF »
Independent {beta}-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2.
H. Wei, S. Ahn, S. K. Shenoy, S. S. Karnik, L. Hunyady, L. M. Luttrell, and R. J. Lefkowitz (2003)
PNAS 100, 10782-10787
   Abstract »    Full Text »    PDF »
Receptor- and Nucleotide Exchange-independent Mechanisms for Promoting G Protein Subunit Dissociation.
M. Ghosh, Y. K. Peterson, S. M. Lanier, and A. V. Smrcka (2003)
J. Biol. Chem. 278, 34747-34750
   Abstract »    Full Text »    PDF »
Involvement of Intramolecular Interactions in the Regulation of G Protein-Coupled Receptor Kinase 2.
S. Sarnago, R. Roca, A. De Blasi, A. Valencia, F. Mayor Jr., and C. Murga (2003)
Mol. Pharmacol. 64, 629-639
   Abstract »    Full Text »    PDF »

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