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

Article

关键词: CRYSTAL-STRUCTURE;    BETA-ARRESTIN;    TERNARY COMPLEX;    LIGAND-BINDING;    CONFORMATION;    STATE;    ENDOCYTOSIS;    MECHANISM;    DOMAIN;   

DOI  :  10.1038/nature12120

来源: SCIE

【 摘 要 】

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(1). G proteins mediate activation of second-messenger-generating enzymes and other effectors, GRKs phosphorylate activated receptors(2), and arrestins subsequently bind phosphorylated receptors and cause receptor desensitization(3). 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(4). Despite their central role in regulation and signalling of GPCRs, a structural understanding of beta-arrestin activation and interaction with GPCRs is still lacking. Here we report the crystal structure of beta-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 beta-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 beta-arrestin-1. The structure of the beta-arrestin-1-V2Rpp-Fab30 complex shows marked conformational differences in beta-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 beta-arrestin-1. These results reveal, at high resolution, a receptor-interacting interface on beta-arrestin, and they indicate a potentially general molecular mechanism for activation of these multifunctional signalling and regulatory proteins.

【 授权许可】

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