2. Academic Validation
  3. Identification of Phosphorylation Codes for Arrestin Recruitment by G Protein-Coupled Receptors

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

  • Cell. 2017 Jul 27;170(3):457-469.e13. doi: 10.1016/j.cell.2017.07.002.
X Edward Zhou 1,  Yuanzheng He 2,  Parker W de Waal 2,  Xiang Gao 2,  Yanyong Kang 2,  Ned Van Eps 3,  Yanting Yin 1,  Kuntal Pal 2,  Devrishi Goswami 4,  Thomas A White 5,  Anton Barty 5,  Naomi R Latorraca 6,  Henry N Chapman 7,  Wayne L Hubbell 8,  Ron O Dror 6,  Raymond C Stevens 9,  Vadim Cherezov 10,  Vsevolod V Gurevich 11,  Patrick R Griffin 4,  Oliver P Ernst 12,  Karsten Melcher 2,  H Eric Xu 13
Affiliations

Affiliations

  • 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: [email protected].
PMID: 28753425 DOI: 10.1016/j.cell.2017.07.002
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.

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