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.


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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Arrestins / chemistry*
  • Arrestins / metabolism
  • Chromatography, Liquid
  • Humans
  • Mice
  • Models, Molecular
  • Phosphorylation
  • Rats
  • Rhodopsin / chemistry*
  • Rhodopsin / metabolism
  • Sequence Alignment
  • Tandem Mass Spectrometry
  • X-Rays


  • Arrestins
  • arrestin 1 protein, mouse
  • Rhodopsin