The N and C lobes are connected by a hinge region, and the finger loop is located near the interface between the N and C lobes 6. Βarrs are composed of N and C lobes, and each forms a β-strand sandwich structure. Thus, the interactions between GPCRs and βarrs are emerging as a focal point for drug discovery, and the details of the conformational states of βarrs bound to GPCRs should be clarified to provide information for developing functionally selective drugs. Recent reports suggested that the multiple functions of βarr, such as desensitization, internalization, and signal transduction, could be separable by mutations of βarrs or ligands bound to GPCRs, and different readouts of βarr functions resulted in distinct pharmacological outcomes 2, 3, 4, 5. The ability of GPCR-bound βarr to engage different scaffolding partners suggests that βarr can adopt multiple conformations, which are modulated by GPCRs 1. The functions of βarrs are driven by scaffolds of various downstream effectors, such as clathrin, adaptin, kinases, and phosphatases. βarr binding to GPCRs elicits multifaceted responses such as receptor desensitization, receptor internalization, and activation of mitogen-activated protein kinases (MAPKs). This plasticity of βarr conformation in complex with GPCRs engaged in different binding modes may explain the multifunctionality of βarrs.Īfter activation by agonist binding, G protein-coupled receptors (GPCRs) are typically phosphorylated at serine and/or threonine residues on their C-terminal region by GPCR kinases (GRKs), and β-arrestins (βarrs) bind to the phosphorylated GPCRs, leading to signal regulation via GPCRs. The conformation-selective antibody, Fab30, promotes partially activated βarr into the activated-like conformation. Our NMR analyses demonstrated that while the C tail-mediated interaction alone induces partial activation, in which βarr exists in equilibrium between basal and activated conformations, the TM core- and the C tail-mediated interactions together completely shift the equilibrium toward the activated conformation. ![]() Here, we show the conformational changes for βarr activation upon the C tail- and TM core-mediated interactions with a prototypical GPCR by nuclear magnetic resonance (NMR) spectroscopy. However, the effects of the C tail- and TM core-mediated interactions on the conformational activation of βarrs have remained elusive. ![]() βarrs typically interact with phosphorylated C-terminal tail (C tail) and transmembrane core (TM core) of GPCRs. Β-arrestins (βarrs) play multifaceted roles in the function of G protein-coupled receptors (GPCRs).
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