Molecular insights into atypical modes of β-arrestin interaction with seven transmembrane receptors

Abstract

β-arrestins are multifunctional proteins that are critically involved in regulating spatio26 temporal aspects of GPCR signaling. The interaction of β-arrestins with GPCRs is typically conceptualized in terms of receptor activation and phosphorylation primarily in the carboxyl terminus. Interestingly however, there are several GPCRs that harbor majority of phosphorylation sites in their 3rd intracellular loop (ICL3) instead of carboxyl-terminus but still robustly engage β-arrestins. Moreover, there are several 7TMRs that are now characterized as intrinsically-biased, β-arrestin-coupled receptors (ACRs) due to lack of functional G protein-coupling but robust β-arrestin binding leading to functional outcomes. The molecular basis of β-arrestin interaction and activation upon binding to these types of 7TMRs is currently elusive, and it represents a major knowledge gap in our current understanding of this signaling system.