Arrestins: Critical Players in Trafficking of Many GPCRs

Abstract

Arrestins specifically bind active phosphorylated G protein-coupled receptors (GPCRs). Receptor binding induces the release of the arrestin C-tail, which in non-visual arrestins contains high-affinity binding sites for clathrin and its adaptor AP2. Thus, serving as a physical link between the receptor and key components of the internalization machinery of the coated pit is the best-characterized function of non-visual arrestins in GPCR trafficking. However, arrestins also regulate GPCR trafficking less directly by orchestrating their ubiquitination and deubiquitination. Several reports suggest that arrestins play additional roles in receptor trafficking. Non-visual arrestins appear to be required for the recycling of internalized GPCRs, and the mechanisms of their function in this case remain to be elucidated. Moreover, visual and non-visual arrestins were shown to directly bind N-ethylmaleimide-sensitive factor, an important ATPase involved in vesicle trafficking, but neither molecular details nor the biological role of these interactions is clear. Considering how many different proteins arrestins appear to bind, we can confidently expect the elucidation of additional trafficking-related functions of these versatile signaling adaptors.

Keywords: Arrestin; GPCR; Internalization; Recycling; Signaling.

Figure 1

Arrestins play many roles in GPCR trafficking. Arrestins (ARR) bind active phos-phorylated GPCRs (shown as a seven-helix bundle). Receptor binding induces the release of the arrestin C-tail, which carries binding sites for clathrin (Clath) and adaptor protein-2 (AP2). The interactions of these sites with clathrin and AP2 promote receptor internalization via coated pits. Arrestins also recruit ubiquitin ligases Mdfm2, Nedd4, and AIP4 to the complex, which favors ubiquitination of both non-visual arrestins and at least some GPCRs. Arrestins also recruit certain deubiquitination enzymes (USP20 and USP33 are shown), facilitating receptor deubiquitination. The role of arrestin interactions with microtubules, centrosome, and N-ethylmaleimide-sensitive factor (NSF) in trafficking of GPCRs and/or other proteins remains to be elucidated.