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

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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.

Introduction

Arrestins were initially discovered in the visual system and include four mammalian members, two visual (arrestin-1 in rod cells and arrestin-4 in cone cells) and two non-visual (β-arrestin1 and β-arrestin2, also called arrestin-2 and arrestin-3, respectively). Arrestins are expressed in metazoans and selectively bind to the agonist-occupied phosphorylated conformation of G protein-coupled receptors (GPCRs) [1]. While arrestins were initially named on the basis of their ability to arrest or turn-off the coupling of GPCRs to heterotrimeric G proteins and thereby inhibit signaling, it is now evident that β-arrestins can also regulate GPCR trafficking as well as G protein-independent signaling [2, 3]. A general scheme for β-arrestin-mediated regulation of GPCR function is depicted in Figure 1.

Interestingly, recent studies have identified two additional families of arrestin related proteins, a group of Vps26-related proteins and α-arrestins. Vps26 is broadly expressed in eukaryotes and is a component of the retromer and has a structure similar to the visual and β-arrestins [4]. The α-arrestins are broadly expressed in all eukaryotes except plants and include 6 mammalian members referred to as arrestin domain-containing (ARRDC) proteins [5, 6•]. Computational modeling suggests that the α-arrestins also have a structure similar to the visual and β-arrestins and several studies have suggested a role for these proteins in GPCR trafficking.

Section snippets

β-Arrestins in GPCR endocytosis

A role for β-arrestins in GPCR trafficking was initially revealed by the demonstration that overexpression of wild type β-arrestins enhanced agonist-promoted internalization of the β2-adrenergic receptor (β2AR) while expression of dominant negative β-arrestin mutants inhibited β2AR internalization [7]. Mechanistic insight into this process was initially provided by the finding that β-arrestin directly interacts with clathrin, a major component of clathrin-coated pits (CCPs) [8]. The primary

Structural insight into β-arrestin-mediated trafficking

While β-arrestin-mediated endocytosis of GPCRs requires interaction with clathrin, AP2 and phosphoinositides, the temporal and spatial dynamics of these interactions are at least partially controlled by conformational changes that occur when β-arrestin binds to a phosphorylated activated GPCR [13, 19, 20]. Arrestins are composed of two major domains, the N-domain and C-domain, which primarily consist of β-sheets and connecting loops with one short α-helix (Figure 2a). There are two major

Role of post-translational modifications of β-arrestin in GPCR trafficking

While the interactions described above are important for arrestin-mediated endocytosis of GPCRs, dynamic post-translational modifications of β-arrestins including phosphorylation, nitrosylation, sumoylation and ubiquitination also regulate the endocytic process. β-Arrestins are basally phosphorylated in the C-tail (e.g. Ser-412 in β-arrestin1), which inhibits interaction with the endocytic machinery, and GPCR binding promotes β-arrestin dephosphorylation and facilitates receptor internalization

Additional interactions involved in β-arrestin-promoted trafficking

The initial studies demonstrating β-arrestin ubiquitination by Mdm2 also revealed that β-arrestins regulate the ubiquitination of the β2AR [31]. β-Arrestin2 was subsequently found to serve as an adaptor between the β2AR and the E3 ubiquitin ligase Nedd4 and facilitate β2AR ubiquitination and trafficking [36, 37]. β-Arrestin recruitment of E3 ubiquitin ligases appears to be a common theme and has also been shown for Smurf2, which interacts with β-arrestin2 to mediate ubiquitination of the

Arrestin domain-containing proteins in GPCR trafficking

Recent studies have revealed an arrestin-related family of proteins called α-arrestins [5]. The α-arrestins are expressed in all eukaryotes except plants and have been most extensively studied in S. cerevisiae and mammals. In S. cerevisiae, there are 10 family members called arrestin-related trafficking adaptors (ART 1-10) that have been shown to play a broad role in regulating the trafficking of various transporters [6•]. A potential role for ARTs in GPCR trafficking has not been reported.

In

α-Arrestins are structurally related to visual/β-arrestins

While α-arrestins have only 11–15% amino acid homology with β-arrestins, modeling studies suggest that the α-arrestins contain an arrestin-fold structure consisting of an arrestin-like N-domain and C-domain and an extended C-tail [6•]. A recent partial structure of the N-terminal domain of TXNIP appears to be more structurally similar to Vps26, a component of the retromer that also adopts an arrestin-fold structure, than to β-arrestins [63]. While it remains to be established whether the

ARRDC localization and interactions

While the ARTs are mainly present in the cytosol [64], the cellular localization differs among the ARRDCs. TXNIP is mainly localized in the nucleus [65] while ARRDC2, 3 and 4 are generally localized on the plasma membrane and endocytic vesicles [37, 60, 62, 66]. ARRDC1 has been reported to be localized at the plasma membrane [37, 60] or on intracellular puncta [67]. It is important to note that most of these observations have been drawn from studying ARRDCs overexpressed in heterologous cell

Conclusions

The arrestin clan can now be broadly divided into three structurally similar subgroups: the visual and β-arrestins, the α-arrestins and the Vps26 proteins. These proteins appear to largely function as adaptors to modulate protein/protein interaction and receptor sorting. Mechanistic insight for the β-arrestins suggests that this process is initially driven by conformational changes that occur upon GPCR binding that drives β-arrestin interactions with the endocytic machinery. While a role for

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank members of the Benovic lab for helpful comments. This work was supported in part by National Institutes of Health grants GM44944, GM47417 and HL114471 to JLB.

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