Emerging structural insights into GPCR–β-arrestin interaction and functional outcomes

Agonist-induced recruitment of β-arrestins (βarrs) to G protein-coupled receptors (GPCRs) plays a central role in regulating the spatio-temporal aspects of GPCR signaling. Several recent studies have provided novel structural and functional insights into our understanding of GPCR–βarr interaction, subsequent βarr activation and resulting functional outcomes. In this review, we discuss these recent advances with a particular emphasis on recognition of receptor-bound phosphates by βarrs, the emerging concept of spatial positioning of key phosphorylation sites, the conformational transition in βarrs during partial to full-engagement, and structural differences driving functional outcomes of βarr isoforms. We also highlight the key directions that require further investigation going forward to fully understand the structural mechanisms driving βarr activation and functional responses. Phosphorylation of GPCRs is a critical determinant for βarr interaction, and emerging data now suggest that even a single phosphorylation site can make a decisive contribution in βarr recruitment and resulting functional outcomes. [Display omitted] •Agonist-induced phosphorylation of GPCRs drive βarr interaction, activation, and resulting functional outcomes.•A single phosphorylation site can have a decisive contribution in βarr recruitment and resulting functional responses.•The transition from tail-engaged to fully-engaged binding mode imparts distinct structural changes in βarrs.•There are receptor-specific and βarr isoform-specific mechanisms driving GPCR–βarr interaction and functional divergence.•Structural details of distinct βarr binding modes, complexes with ACRs, and catalytic activation remain to be visualized.