Structural and functional insights into rhodopsin‐like and secretin‐like GPCR –arrestin interactions and regulation

Structural and functional studies of arrestins have revealed their essential role as multifunctional regulators of G protein‐coupled receptor (GPCR) signaling, desensitization, and trafficking. Despite significant challenges in capturing the dynamic nature of GPCR–arrestin interactions, great progress has been made in recent years, particularly through cryo‐electron microscopy (cryo‐EM) and X‐ray crystallography that allowed structural characterization of arrestins in both their basal and GPCR‐bound‐like conformation and of GPCR–arrestin complexes in fully and partially engaged conformations. These structural insights have advanced our understanding of the molecular mechanisms underlying arrestin transition to the GPCR‐bound conformation and its selective engagement by different GPCRs. The phosphorylation‐dependent ‘barcode’ hypothesis further explains how specific patterns of receptor phosphorylation can encode differential arrestin recruitment and functional specificity. We discussed various biophysical techniques including nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and fluorescence‐based assays that have been used to investigate arrestin conformational dynamics and GPCR interactions in vitro and in live cells.