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We recently published “Sortase ligation enables homogeneous GPCR phosphorylation to reveal diversity in β-arrestin coupling” in Proceedings of the National Academy of Sciences.

β-Arrestin regulates G protein-coupled receptor (GPCR) signaling by interacting with two regions of agonist-activated receptors—the phosphorylated C terminus and the seven transmembrane helix bundle. The phosphorylation pattern on GPCRs is thought to be the primary driver of β-arrestin binding affinity and functional consequences. To more effectively delineate the relative contributions of these two interactions, we present an innovative strategy to homogeneously phosphorylate purified GPCRs—enzymatic ligation of a synthetic phosphopeptide. This approach unexpectedly revealed that different receptors with identical phosphorylation patterns exhibit dramatic variability in their ability to couple to β-arrestin through the transmembrane core. These differences could play an important role in tuning the balance of G protein- and β-arrestin–mediated cellular signaling pathways stimulated by each GPCR.