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- and β-arrestins with a focus on our current understanding of how these adaptor proteins regulate GPCR trafficking.
Keywords: arrestin, receptor, phosphorylation, endocytosis, clathrin, adaptin, phosphoinositides
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 Fig. 1.
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).
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.
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 clathrin binding site in β-arrestins was found to be a clathrin binding box (LIELD in β-arrestin1) localized in the C-terminal region [9], while a secondary clathrin binding site (LLGDL) was identified in a splice variant of β-arrestin1 [10]. Additional mechanistic insight was provided by the demonstration that β-arrestins also interact with the endocytic adaptor AP2 [11,12], which normally functions to promote the assembly of clathrin lattices and targets receptors to CCPs. This interaction is mediated by an adaptin binding motif in the C-tail of β-arrestins that binds to the β2-subunit of AP2 [12–16]. While the ability of β-arrestins to interact with clathrin and AP2 is essential in arrestin-mediated endocytosis of GPCRs [10,12,13], β-arrestin interaction with phosphoinositides also plays a critical role in this process [17]. Interestingly, β-arrestins contain two phosphoinositide binding sites and interaction with inositol hexakisphosphate (IP6) regulates homo- and hetero-oligomerization and ultimately the cellular localization and function of β-arrestins [18]. The regions of β-arrestin1 involved in clathrin, AP2 and phosphoinositide binding are depicted in Fig. 2A.
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).
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- and C-domain, which primarily consist of β-sheets and connecting loops with one short α-helix (Fig. 2A). There are two major intra-molecular interactions that maintain arrestins in this basal conformation, a polar core of charged residues that connects the N-terminus, N- and C-domains and C-tail and a 3-element region that connects the N-terminus, α-helix and C-tail [1]. The binding of arrestin to an activated phosphorylated GPCR is believed to disrupt these intra-molecular constraints thereby releasing the C-tail and promoting β-arrestin interaction with clathrin and AP2. While several lines of evidence support this proposed model [13,16,19–26], the recent crystallographic structure of β-arrestin1 bound to a V2 vasopressin receptor phosphopeptide perhaps provides the most compelling evidence to date [27]. Importantly, the receptor phosphopeptide binds to Lys-10 and Lys-11, disrupting the 3-element region and displacing the C-tail of β-arrestin1. The displacement of the C-tail by the phosphopeptide as well as the large movement of connecting loops also results in a significant twist of the N- and C-domains relative to each other (Fig. 2B) [27].
Ultimately, the release of the C-tail of β-arrestin facilitates binding to clathrin and AP2 [13,16,19,20]. While the C-tail is not visible in the β-arrestin1/phosphopeptide structure [27], the β2-adaptin binding region in β-arrestin is thought to transition from a β-sheet in the basal state of the protein to an α-helix when associated with β2-adaptin [14–16]. This conformational change has been suggested to function as a molecular switch to stabilize the activated conformation of β-arrestin [14,15,27]. Taken together, rearrangement of various domains in the active state of β-arrestin optimizes arrestin-receptor interaction and facilitates β-arrestin interaction with endocytic proteins by releasing the C-tail. Crystal structures of holo-arrestin/GPCR complexes with and without clathrin and β2-adaptin will be needed to more fully define how arrestins discriminate activated phosphorylated GPCRs and how GPCR binding promotes association with the endocytic machinery.
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 [28]. β-arrestin2 interaction with endothelial nitric oxide synthase promotes S-nitrosylation at Cys-410 and enhances β-arrestin2 association with CCPs and accelerates GPCR internalization [29]. Interestingly, sumoylation of β-arrestin2 was recently shown to occur on Lys-400 upon β2AR activation and also facilitate internalization [30]. A common theme in each of these modifications is that they occur in the β-arrestin C-tail, a region involved in stabilizing intra-molecular interactions and ultimately the region that directly interacts with the endocytic machinery (Fig. 2A).
β-arrestin ubiquitination by the E3 ubiquitin ligase Mdm2 appears to be a particularly important modification in regulating arrestin function. This modification is driven by GPCR activation as first noted for the β2AR and ultimately plays a role in stabilizing the β-arrestin/GPCR complex [31], although β-arrestin ubiquitination does not appear to have a direct effect on receptor binding [32]. An interesting feature of this modification is that the sites of ubiquitination appear to be dictated by the specific GPCR involved. For example, β-arrestin binding to the AT1a receptor promotes ubiquitination of Lys-11 and 12 in β-arrestin, binding to the V2 vasopressin receptor promotes ubiquitination of Lys-18, 107, 108, 207 and 296, and binding to the β2AR promotes ubiquitination that is not site-specific [32,33]. The removal of ubiquitin is also dynamic since β-arrestins bind deubiquitinases (DUBs) such as UPS20 and USP33 in a process regulated by GPCR activation. Importantly, a knockdown of USP20 and USP33 enhances β-arrestin2 ubiquitination and increases β2AR degradation [34,35]. Ultimately, the dynamics and site-specificity of β-arrestin ubiquitination appears to play a critical role in regulating the stability of β-arrestin/GPCR complexes as well as downstream processes such as GPCR trafficking and signaling.
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 μ-opioid receptor and regulate CCP maturation [38], and AIP4, which interacts with β-arrestin1 on early endosomes and facilitates the sorting and degradation of the chemokine receptor CXCR4 [39]. Interestingly, β-arrestins also directly interact with the E3 ubiquitin ligase parkin and while this interaction enhances β-arrestin binding to Mdm2, it ultimately decreases β-arrestin ubiquitination [40]. Thus, β-arrestins function as adaptors for a variety of E3 ubiquitin ligases to regulate receptor ubiquitination and sorting.
β-arrestins also bind several additional proteins that regulate GPCR trafficking (Table 1). For example, β-arrestin1 interacts with N-ethylmaleimide-sensitive fusion protein (NSF) in an ATP-dependent manner and regulates β2AR trafficking [41]. β-arrestin1 interaction with Arf6-GDP and its nucleotide exchange factors, ARNO and EFA6, results in Arf6 activation and subsequent regulation of GPCR endocytosis and recycling [42–44]. β-arrestin1 and 2 interaction with the Arf GTPase activating protein AGAP2 facilitates β-arrestin association with the β2AR and regulates β2AR recycling [45] while interaction of PIP5K-1α with β-arrestin2 facilitates β2AR endocytosis [46]. β-arrestin1 interaction with signal-transducing adaptor molecule-1 (STAM-1), a component of ESCRT-0, regulates CXCR4 sorting by regulating the ubiquitination of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) [47]. β-arrestin1 also interacts with the Na+/H+ exchanger regulatory factor 1 (NHERF1) to facilitate the agonist-promoted internalization of the P2Y12 receptor [48].
Table 1.
β-arrestin and arrestin-domain containing protein interactions that function in GPCR trafficking
Binding Partner | Functional Role | References |
---|---|---|
β-arrestins | ||
β2-adaptin | Directly interacts with β-arrestins and facilitates GPCR endocytosis | Laporte et al. 2001 Edeling et al. 2006 Schmid et al. 2006 |
μ2-adaptin | Preferentially interacts with β-arrestin2 and facilitates endocytosis of the β2AR | Marion et al. 2007 |
Clathrin | Directly interacts with β-arrestins and facilitates GPCR endocytosis |
Goodman et al. 1996 ter Haar et al. 2000 Kang et al. 2009 |
PIP2 | Directly interacts with β-arrestins and enhances GPCR endocytosis |
Gaidarov et al. 1999 Nelson et al. 2008 |
PIP5K-Iα | Directly interacts with β-arrestin2 and facilitates β2AR endocytosis | Nelson et al. 2008 |
IP6 | Directly interacts with β-arrestins; inhibits β-arrestin/GPCR interaction; facilitates β- arrestin oligomerization; regulates β-arrestin cellular localization |
Gaidarov et al. 1999 Storez et al. 2005 Milano et al. 2006 |
PI3K | Regulates β2AR endocytosis by AP2 recruitment to the β2AR/β-arrestin complex | Naga Prasad et al. 2002 |
NSF | Directly interacts with β-arrestin2 and enhances endocytosis of the β2AR | McDonald et al. 1999 |
ARF6 | GDP-bound form interacts with β-arrestin1 and enhances GPCR endocytosis and degradation and negatively controls recycling |
Claing et al. 2001 Houndolo et al. 2005 Macia et al. 2012 |
ARNO | Activates ARF6 and facilitates β-arrestin release from the luteinizing hormone/choriogonadotropin receptor | Mukherjee et al. 2000 |
EFA6 | β-arrestin1 binds ARF6-GDP and EFA6 and facilitates ARF6 activation leading to β2AR degradation | Macia et al. 2012 |
AGAP2 | AGAP2 interacts with β-arrestin1 and 2 and facilitates β-arrestin association with the β2AR and regulates β2AR recycling | Wu et al., 2013 |
Mdm2 | Ubiquitinates β-arrestin2 and facilitates the endocytosis of β2AR |
Shenoy et al. 2001 Song et al, 2007 |
parkin | Directly interacts with β-arrestin and facilitates Mdm2 interaction | Ahmed at al., 2011 |
AIP4 | Interacts with β-arrestin2 on early endosomes and facilitates CXCR4 degradation | Bhandari et al. 2007 |
Nedd4 | Interacts with β-arrestin to facilitate β2AR ubiquitination and trafficking |
Shenoy et al. 2008 Han et al. 2013 |
Smurf2 | Interacts with β-arrestin2 and mediates μ-opioid receptor ubiquitination and trafficking | Henry et al., 2012 |
USP20 | Directly deubiquitinates β-arrestin2 and β2AR to prevent receptor degradation | Shenoy et al. 2009 |
USP33 | Directly deubiquitinates β-arrestin2 and β2AR to prevent receptor degradation | Berthouze et al. 2009 |
STAM-1 | Interacts with β-arrestin1 to regulate CXCR4 sorting | Malik & Marchese 2010 |
eNOS | Interacts with and s-nitrosylates β-arrestin2 and facilitates β-arrestin2 binding with clathrin and β-adaptin; promotes receptor internalization | Ozawa et al. 2008 |
NHERF | Interacts with β-arrestin1 to regulate P2Y12 receptor internalization | Nisar et al. 2012 |
Arrestin-domain containing proteins (ARRDCs) | ||
Nedd4 | Directly interacts with the PPXY motifs of ARRDC3 to promote β2AR ubiquitination and degradation ARRDC3 interacts with Nedd4-β2AR upon agonist stimulation to recruit the complex to endosomes |
Nabhan et al. 2010 Han et al. 2013 |
β-arrestins | Form heterodimers with ARRDC1 to mediate Notch ubiquitination and degradation | Puca et al. 2013 |
Itch/AIP4 | Interacts with ARRDC3 Interacts with ARRDC2, ARRDC3 and TXNIP Interacts with ARRDC1 to mediate Notch ubiquitination and degradatio |
Nabhan et al. 2010 Rauch et al. 2011 Puca et al. 2013 |
ALIX | Interacts with ARRDC1, 2 and 3 via its proline-rich domain (PRR) | Rauch et al. 2011 |
HRS | Interacts with the PPXY motifs of ARRDC3 |
Han et al. 2013 Shea et al. 2013 |
Clathrin | Interacts with ARRDC3/4 under basal conditions, interaction decreases upon agonist stimulation | Shea et al. 2013 |
WWP1 | Interacts with all five ARRDCs |
Nabhan et al. 2010 Rauch et al. 2011 |
WWP2 | Interacts with all ARRDCs except ARRDC4 |
Nabhan et al. 2010 Rauch et al. 2011 |
While β-arrestins regulate the trafficking of many GPCRs, they also appear to function as broad-based endocytic adaptors to regulate the trafficking of many other proteins including the IGF1 receptor [49,50], type III TGF-β receptor [51], Frizzled [52], Notch [53,54], TRPV1 [55], TRPV4 [56], Aph-1a [57], VE-cadherin [58] and the Na+/H+ exchanger NHE5 [59]. Thus, β-arrestins appear to have a broad role in regulating the trafficking of many receptors and channels.
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 mammals, there are 6 α-arrestins, named ARRDC1-5 and thioredoxin-interacting protein (TXNIP). While there have been relatively few studies characterizing a role for ARRDC proteins in regulating GPCR trafficking, ARRDC3 was identified in a screen for proteins involved in regulating β2AR degradation [60]. This study reported that ARRDC3 interacts with the β2AR in an agonist-dependent manner at the plasma membrane and serves as an adaptor to facilitate Nedd4-mediated β2AR ubiquitination and degradation. Moreover, mutation of the two PPXY motifs in ARRDC3 disrupted interaction with Nedd4 and attenuated β2AR ubiquitination and degradation [60]. Characterization of a mouse ARRDC3 knockout revealed a role for ARRDC3 in metabolism and suggested that ARRDC3 interaction with the β2AR and β3AR plays a role in this process [61]. An additional study confirmed the ability of ARRDC3 to co-immunoprecipitate with the β2AR and provided evidence that ARRDC3 mediates β2AR ubiquitination [62]. These authors also showed that the V2 vasopressin receptor co-immunoprecipitated with ARRDC4. While these results are intriguing, a more recent study reported that overexpression or depletion of ARRDC3 did not affect the ubiquitination, internalization or degradation of the β2AR [37]. These authors found that ARRDC3, along with ARRDC2 and ARRDC4, localized on early endosomes and proposed that these proteins serve as secondary adaptors to recruit the internalized β2AR/β-arrestin/Nedd4 complex to a subset of early endosomes. Thus, ARRDC proteins appear to regulate GPCR trafficking although the detailed mechanisms remain to be more fully dissected (Fig. 1).
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 arrestin-like N- and C-domains 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 α-arrestins are structurally related to visual/β-arrestins, sequence analysis suggests some fundamental differences between these protein families that might differentiate their function. First, the α-arrestins appear to lack a “polar core”, which normally maintains visual/β-arrestins in a basal conformation and is crucial for their receptor phospho-sensing activity and release of the C-tail upon receptor binding [1,27]. The lack of a “polar core” might suggest that α-arrestins would not be sensitive to the phosphorylation state of a GPCR or, at least, not in a manner similar to visual/β-arrestins. Another distinguishing feature of the α-arrestins, except for ARRDC5, is that they contain two PPXY motifs in an extended C-tail. PPXY motifs can interact with WW-domains that are commonly found in E3 ubiquitin ligases and, as described in more detail below, the ARRDCs do interact with a number of E3 ubiquitin ligases.
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 lines. Thus, it will be important to characterize the localization of the endogenous ARRDCs.
Similar to the β-arrestins, ARRDCs appear to interact with other proteins and thereby function as adaptors. These include interactions with various HECT-domain E3 ubiquitin ligases such as WWP1, WWP2, Nedd4, and Itch/AIP4, via the WW domain on the ligase and the PPXY motifs on the ARRDC (Table 1) [37,60,62,66,68]. Similarly, many ARRDCs interact with components of the ESCRT machinery. For example, ARRDC1 interacts with ALIX and VPS4, ESCRT-I and ESCRT-III associated proteins, respectively, and Tsg101, a component of the ESCRT-I complex [67,68]. Deletion of ARRDC1 C-tail abrogates interaction with ALIX and Tsg101 but does not affect VPS4 interaction [67]. ARRDC2 also interacts with ALIX while ARRDC3 interacts with ALIX and HRS, a component of the ESCRT-0 complex, and mutation of its PPXY motifs or deletion of the C-tail disrupts these interactions [37,67]. Those observations suggest a role for the ARRDCs in regulating trafficking via their ability to interact with the ESCRT machinery.
Recent studies have also suggested that the ARRDCs can heterodimerize with β-arrestins. For example, overexpressed ARRDC3 and ARRDC4 appear to co-immunoprecipitate with endogenous β-arrestins independent of receptor activation [62]. In addition, ARRDC1 has been shown to form a heterodimer with β-arrestins, interact with Notch and Itch (AIP4), and together with β-arrestins, regulate Notch ubiquitination and degradation [54]. Overexpression of an ARRDC1 PPXY mutant inhibited Itch mediated Notch ubiquitination and degradation and also led to a significant increase in Notch/β-arrestin1 interaction, presumably due to insufficient Notch degradation.
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 the α-arrestins in GPCR trafficking has not been as well defined, it is evident that the α-arrestins can also function as adaptors for E3 ubiquitin ligases and the ESCRT machinery. It will be important to further dissect the interplay between and α- and β-arrestins in regulating GPCR trafficking as well as gain additional structural insight into the various interactions that modulate these functions.
Acknowledgments
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.
Footnotes
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