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Cell. 2017 Jul 27;170(3):457-469.e13. doi: 10.1016/j.cell.2017.07.002.

Identification of Phosphorylation Codes for Arrestin Recruitment by G Protein-Coupled Receptors.

Author information

1
VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
2
Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
3
Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
4
Department of Molecular Medicine, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
5
Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany.
6
Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University, Stanford, CA 94305, USA; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA; Biophysics Program, Stanford University, Stanford, CA 94305, USA.
7
Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, 22607 Hamburg, Germany; Centre for Ultrafast Imaging, 22761 Hamburg, Germany.
8
Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA.
9
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA; iHuman Institute, ShanghaiTech University, 2F Building 6, 99 Haike Road, Pudong New District, Shanghai 201210, China.
10
Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
11
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
12
Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
13
VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, MI 49503, USA. Electronic address: eric.xu@vai.org.

Abstract

G protein-coupled receptors (GPCRs) mediate diverse signaling in part through interaction with arrestins, whose binding promotes receptor internalization and signaling through G protein-independent pathways. High-affinity arrestin binding requires receptor phosphorylation, often at the receptor's C-terminal tail. Here, we report an X-ray free electron laser (XFEL) crystal structure of the rhodopsin-arrestin complex, in which the phosphorylated C terminus of rhodopsin forms an extended intermolecular β sheet with the N-terminal β strands of arrestin. Phosphorylation was detected at rhodopsin C-terminal tail residues T336 and S338. These two phospho-residues, together with E341, form an extensive network of electrostatic interactions with three positively charged pockets in arrestin in a mode that resembles binding of the phosphorylated vasopressin-2 receptor tail to β-arrestin-1. Based on these observations, we derived and validated a set of phosphorylation codes that serve as a common mechanism for phosphorylation-dependent recruitment of arrestins by GPCRs.

KEYWORDS:

GPCR; GRK; arrestin; biased signaling; drug discovery; membrane proteins; phosphorylation codes; rhodopsin

PMID:
28753425
PMCID:
PMC5567868
DOI:
10.1016/j.cell.2017.07.002
[Indexed for MEDLINE]
Free PMC Article

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