Abstract
Desensitization, signaling, and trafficking of G-protein-coupled receptors (GPCRs) are critically regulated by multifunctional adaptor proteins, β-arrestins (βarrs). The two isoforms of βarrs (βarr1 and 2) share a high degree of sequence and structural similarity; still, however, they often mediate distinct functional outcomes in the context of GPCR signaling and regulation. A mechanistic basis for such a functional divergence of βarr isoforms is still lacking. By using a set of complementary approaches, including antibody-fragment-based conformational sensors, we discover structural differences between βarr1 and 2 upon their interaction with activated and phosphorylated receptors. Interestingly, domain-swapped chimeras of βarrs display robust complementation in functional assays, thereby linking the structural differences between receptor-bound βarr1 and 2 with their divergent functional outcomes. Our findings reveal important insights into the ability of βarr isoforms to drive distinct functional outcomes and underscore the importance of integrating this aspect in the current framework of biased agonism.
Highlights
G-protein-coupled receptors (GPCRs) constitute a large family of integral membrane proteins in the human genome (Bjarnadottir et al, 2006) and a major class of drug targets (Santos et al, 2017)
For most GPCRs, both isoforms of barrs are typically recruited upon agonist stimulation and participate in desensitization, endocytosis, and signaling
Emerging data suggest that a significant level of functional divergence between barr1 and 2 exits for most GPCRs, and in some cases, they even display functional antagonism (Figure 1A) (Srivastava et al, 2015; Hara et al, 2011; Ahn et al, 2003)
Summary
G-protein-coupled receptors (GPCRs) constitute a large family of integral membrane proteins in the human genome (Bjarnadottir et al, 2006) and a major class of drug targets (Santos et al, 2017). GPCRs couple to heterotrimeric G proteins followed by the generation of second messengers and downstream signaling. They are phosphorylated in their carboxyl-terminus and intracellular loops, which results in coupling of b-arrestins (barrs). For most GPCRs, both isoforms of barrs are typically recruited upon agonist stimulation and participate in desensitization, endocytosis, and signaling. The functional differences of barr isoforms is manifested at the level of physiological outcomes downstream of several GPCRs (Srivastava et al, 2015; Walters et al, 2009; Trivedi et al, 2013)
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