Advances in the molecular understanding of GPCR-arrestin complexes

Arrestins are essential proteins for the regulation of G protein-coupled receptors (GPCRs). They mediate GPCR desensitization after the activated receptor has been phosphorylated by G protein receptor kinases (GRKs). In addition, GPCR-arrestin interactions may trigger signaling pathways that are distinct and independent from G proteins. The non-visual GPCRs encompass hundreds of receptors with varying phosphorylation patterns and amino acid sequences, which are regulated by only two human non-visual arrestin isoforms. This review describes recent findings on GPCR-arrestin complexes, obtained by structural techniques, biophysical, biochemical, and cellular assays. The solved structures of complete GPCR-arrestin complexes are of limited resolution ranging from 3.2 to 4.7 Å and reveal a high variability in the relative receptor-arrestin orientation. In contrast, biophysical and functional data indicate that arrestin recruitment, activation and GPCR-arrestin complex stability depend on the receptor phosphosite sequence patterns and density. At present, there is still a manifest lack of high-resolution structural and dynamical information on the interactions of native GPCRs with both GRKs and arrestins, which could provide a detailed molecular understanding of the genesis of receptor phosphorylation patterns and the specificity GPCR-arrestin interactions. Such insights seem crucial for progress in the rational design of advanced, arrestin-specific therapeutics.