GPCRs, the largest family of signal

GPCRs, the largest family of signalling receptors, regulate essentially every physiological process and comprise an important class of drug targets1,2,3,4. GPCR-mediated signalling and regulatory events occur primarily through interactions of the receptor with two classes of transducer protein, heterotrimeric G proteins and β-arrestins. β-arrestins were discovered through their ability to prevent coupling of G proteins to GPCRs and are now known to support additional functions, including endocytosis of GPCRs, mediated by clathrin-coated structures, and downstream signalling, mediated by MAP (mitogen-activated protein) kinase cascades5,6. A long-standing view is that all of these functions occur from a stable and stoichiometric GPCR–β-arrestin complex, the formation of which requires β-arrestin binding to the phosphorylated GPCR tail7,8. There is emerging evidence that GPCR–β-arrestin complexes can vary in structure but, nevertheless, present concepts of cellular β-arrestin function require the formation of a GPCR–β-arrestin complex driven largely by the phosphorylated GPCR tail