Role of β-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 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 α-arrestins have also recently been implicated in regulating GPCR trafficking while Vps26 regulates retrograde trafficking. In this review, we provide an overview of the α-arrestins and β-arrestins with a focus on our current understanding of how these adaptor proteins regulate GPCR trafficking.

Figure 1. Model of β-arrestin and ARRDC-promoted trafficking of GPCRs

(1) Agonist binding to GPCR leads to dissociation of DUBs, heterotrimeric G protein activation and GRK-mediated phosphorylation of the GPCR. (2) β-arrestin, which basally binds to E3 ubiquitin ligases such as Mdm2, interacts with the activated/phosphorylated GPCR which promotes β-arrestin ubiquitination as well as (3) E3 ligase recruitment to β-arrestin and subsequent GPCR ubiquitination. There is also some evidence that ARRDC3 facilitates GPCR ubiquitination. (4) The conformational change in β-arrestin induced by binding to activated/phosphorylated GPCRs promotes the recruitment of the GPCR/β-arrestin complex to clathrin-coated pits and (5) mediates GPCR endocytosis to early endosomes. (6) Some endocytosed GPCRs are quickly deubiquitinated and dephosphorylated by DUBs and protein phosphatases, respectively. (7) GPCRs are then sorted to sorting endosomes and (8) then move to recycling endosomes and (9) recycle back to the plasma membrane. (10) Some GPCR/β-arrestin complexes move to the sorting endosome without being deubiquitinated and dephosphorylated and a subset of these may be recruited by ARRDC3. (11) The ESCRT-complex and its accessory proteins are recruited to the GPCR/β-arrestin-containing sorting endosomes to facilitate GPCR degradation in lysosomes (12 and 13).

Figure 2. Structure of β-arrestin1 annotated with interactions that mediate GPCR trafficking

A. Ribbon diagram of β-arrestin-1L (residues 6 to 399) indicating the N- and C-domains, the polar core and binding sites for the GPCR, phosphoinositides (high affinity site in C-domain and low affinity site in N-domain), clathrin (Lx[D/E] and [L/I]₂GxL motifs) and β2-adaptin ([D/E]xxFxx[F/L]xxxR motif) (PDB: 1JSY and 3GD1) B. Comparison of apo-β-arrestin1 (left) and phosphopeptide-bound β-arrestin1 (right) reveals that the phosphopeptide (blue) displaces the β-arrestin C-tail and disrupts the polar core that is centered around Arg169 (4JQI).