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Role of ?-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking.

ABSTRACT: The arrestin clan can now be broadly divided into three structurally similar subgroups: the originally identified arrestins (visual and ?-arrestins), the ?-arrestins and a group of Vps26-related proteins. The visual and ?-arrestins selectively bind to agonist-occupied phosphorylated G protein-coupled receptors (GPCRs) and inhibit GPCR coupling to heterotrimeric G proteins while the ?-arrestins also function as adaptor proteins to regulate GPCR trafficking and G protein-independent signaling. The ?-arrestins have also recently been implicated in regulating GPCR trafficking while Vps26 regulates retrograde trafficking. In this review, we provide an overview of the ?-arrestins and ?-arrestins with a focus on our current understanding of how these adaptor proteins regulate GPCR trafficking.

SUBMITTER: Kang DS

PROVIDER: S-EPMC3971387 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Publications

Role of β-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking.

Kang Dong Soo DS Tian Xufan X Benovic Jeffrey L JL

Current opinion in cell biology 20131214

The arrestin clan can now be broadly divided into three structurally similar subgroups: the originally identified arrestins (visual and β-arrestins), the α-arrestins and a group of Vps26-related proteins. The visual and β-arrestins selectively bind to agonist-occupied phosphorylated G protein-coupled receptors (GPCRs) and inhibit GPCR coupling to heterotrimeric G proteins while the β-arrestins also function as adaptor proteins to regulate GPCR trafficking and G protein-independent signaling. The ...[more]

PMID: 24680432

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Project description:G-protein-coupled receptors (GPCRs) are critically regulated by ?-arrestins, which not only desensitize G-protein signalling but also initiate a G-protein-independent wave of signalling. A recent surge of structural data on a number of GPCRs, including the ?2 adrenergic receptor (?2AR)-G-protein complex, has provided novel insights into the structural basis of receptor activation. However, complementary information has been lacking on the recruitment of ?-arrestins to activated GPCRs, primarily owing to challenges in obtaining stable receptor-?-arrestin complexes for structural studies. Here we devised a strategy for forming and purifying a functional human ?2AR-?-arrestin-1 complex that allowed us to visualize its architecture by single-particle negative-stain electron microscopy and to characterize the interactions between ?2AR and ?-arrestin 1 using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and chemical crosslinking. Electron microscopy two-dimensional averages and three-dimensional reconstructions reveal bimodal binding of ?-arrestin 1 to the ?2AR, involving two separate sets of interactions, one with the phosphorylated carboxy terminus of the receptor and the other with its seven-transmembrane core. Areas of reduced HDX together with identification of crosslinked residues suggest engagement of the finger loop of ?-arrestin 1 with the seven-transmembrane core of the receptor. In contrast, focal areas of raised HDX levels indicate regions of increased dynamics in both the N and C domains of ?-arrestin 1 when coupled to the ?2AR. A molecular model of the ?2AR-?-arrestin signalling complex was made by docking activated ?-arrestin 1 and ?2AR crystal structures into the electron microscopy map densities with constraints provided by HDX-MS and crosslinking, allowing us to obtain valuable insights into the overall architecture of a receptor-arrestin complex. The dynamic and structural information presented here provides a framework for better understanding the basis of GPCR regulation by arrestins.

Dataset Information

Role of ?-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking.

Publications

Role of β-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking.

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