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Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide.

  • Author(s): Shukla, Arun K;
  • Manglik, Aashish;
  • Kruse, Andrew C;
  • Xiao, Kunhong;
  • Reis, Rosana I;
  • Tseng, Wei-Chou;
  • Staus, Dean P;
  • Hilger, Daniel;
  • Uysal, Serdar;
  • Huang, Li-Yin;
  • Paduch, Marcin;
  • Tripathi-Shukla, Prachi;
  • Koide, Akiko;
  • Koide, Shohei;
  • Weis, William I;
  • Kossiakoff, Anthony A;
  • Kobilka, Brian K;
  • Lefkowitz, Robert J
  • et al.
Abstract

The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second-messenger-generating enzymes and other effectors, GRKs phosphorylate activated receptors, and arrestins subsequently bind phosphorylated receptors and cause receptor desensitization. Arrestins activated by interaction with phosphorylated receptors can also mediate G-protein-independent signalling by serving as adaptors to link receptors to numerous signalling pathways. Despite their central role in regulation and signalling of GPCRs, a structural understanding of β-arrestin activation and interaction with GPCRs is still lacking. Here we report the crystal structure of β-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). This peptide has previously been shown to functionally and conformationally activate β-arrestin-1 (ref. 5). To capture this active conformation, we used a conformationally selective synthetic antibody fragment (Fab30) that recognizes the phosphopeptide-activated state of β-arrestin-1. The structure of the β-arrestin-1-V2Rpp-Fab30 complex shows marked conformational differences in β-arrestin-1 compared to its inactive conformation. These include rotation of the amino- and carboxy-terminal domains relative to each other, and a major reorientation of the 'lariat loop' implicated in maintaining the inactive state of β-arrestin-1. These results reveal, at high resolution, a receptor-interacting interface on β-arrestin, and they indicate a potentially general molecular mechanism for activation of these multifunctional signalling and regulatory proteins.

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