Receptor-Arrestin Interactions: The GPCR Perspective

Abstract

Arrestins are a small family of four proteins in most vertebrates that bind hundreds of different G protein-coupled receptors (GPCRs). Arrestin binding to a GPCR has at least three functions: precluding further receptor coupling to G proteins, facilitating receptor internalization, and initiating distinct arrestin-mediated signaling. The molecular mechanism of arrestin–GPCR interactions has been extensively studied and discussed from the “arrestin perspective”, focusing on the roles of arrestin elements in receptor binding. Here, we discuss this phenomenon from the “receptor perspective”, focusing on the receptor elements involved in arrestin binding and emphasizing existing gaps in our knowledge that need to be filled. It is vitally important to understand the role of receptor elements in arrestin activation and how the interaction of each of these elements with arrestin contributes to the latter’s transition to the high-affinity binding state. A more precise knowledge of the molecular mechanisms of arrestin activation is needed to enable the construction of arrestin mutants with desired functional characteristics.

Lipids and Phosphorylation Conjointly Modulate Complex Formation of β2-Adrenergic Receptor and β-arrestin2

“…GPCRs interact with signaling molecules through distinct structural elements. The highly dynamic, disordered and little conserved intracellular loop 3 (ICL3) and C-terminus of the receptors have been reported to play important roles in binding G proteins, GRKs and arrestins ( Chee et al, 2008 ; Komolov et al, 2017 ; Yin et al, 2019 ; Seyedabadi et al, 2021 ). The dynamics of these disordered regions was shown to be reduced by the presence of interacting proteins, suggesting a disorder-to-order transition.…”

Agonist-induced phosphorylation of orthologues of the orphan receptor GPR35 functions as an activation sensor

“…A general concern in the development of therapeutic programs based on agonist ligands is the, at least theoretical, potential to induce desensitization or tachyphylaxis with sustained exposure to the ligand. Given the well-known roles of agonist-induced phosphorylation in arrestin interactions with many GPCRs ( 9 , 10 , 11 , 12 ) and the roles of arrestins in receptor desensitization and internalization from the surface of cells ( 13 ) it is perhaps surprising that detailed analyses of the sites and mechanisms of agonist-regulated phosphorylation of GPR35, and how this might vary between human and rodent orthologues, has not been reported. Herein, we address this for each of human, mouse, and rat GPR35, using combinations of mass spectrometry, to define amino acids that become phosphorylated in an agonist-dependent manner and both [ 32 P] incorporation and mutagenesis to define the contribution of these to arrestin-3 interactions.…”

DEER Analysis of GPCR Conformational Heterogeneity

“…This finding suggests that either the receptor or the transducer exist in more than one conformation, a hint at different architectures of this complex with potentially distinct function [ 31 , 93 ]. DEER, due to its superior applicability to large, structural heterogeneous proteins and protein complexes, represents a predestined experimental method to track down those alternative “flavors” [ 94 ].…”