A Model for Arrestin’s Regulation: The 2.8 Å Crystal Structure of Visual Arrestin

Hirsch, Joel A.; Schubert, Carsten J.; Gurevich, Vsevolod V.; Sigler, Paul B.

doi:10.1016/s0092-8674(00)80735-7

Cited by 395 publications

(418 citation statements)

References 59 publications

(4 reference statements)

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“…Arrestin/Receptor Interaction and Receptor Internalization-The current model for the understanding of arrestin interaction with the receptor is based on rhodopsin studies and the recent crystal structures of visual arrestin and ␤-arrestin (12,13,43). The model proposes that an initial binding of arrestin to the phosphorylated residues in the carboxyl tail of the receptor disrupt intramolecular charge-charge interactions between highly basic residues in arrestin.…”

Section: Discussionmentioning

confidence: 99%

“…The current model for the understanding of the arrestinreceptor interaction mechanism is based on various studies of visual arrestin interaction with rhodopsin (11)(12)(13)(14)(15)(16). Visual arrestin binding with rhodopsin requires GRK-1 phosphorylated residues, and the contact of phosphorylated residues with a cationic region of arrestin switches it into an active conformation, enabling interaction with an exposed binding site on activated rhodopsin.…”

Section: Agonist Binding To Most G Protein-coupled Receptorsmentioning

confidence: 99%

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Internalization Determinants of the Parathyroid Hormone Receptor Differentially Regulate β-Arrestin/Receptor Association

Vilardaga

Krasel

Chauvin

et al. 2002

Journal of Biological Chemistry

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␤-Arrestins have been implicated in regulating internalization of the parathyroid hormone receptor (PTHR), but the structural features in the receptor required for this effect are unknown. In the present study performed in HEK-293 cells, we demonstrated that different topological domains of PTHR are implicated in agonist-dependent receptor internalization; truncation of the cytoplasmic tail (PTHR-TR), selective mutations of the cytoplasmic tail to remove the sites of parathyroid hormone (PTH)-stimulated phosphorylation (PTHR-PD), and mutations in the third transmembrane helix (N289A) or in the third cytoplasmic loop (K382A) resulted in a 30 -60% reduction in 125 I-PTH-related protein internalization. To better define the role of these internalization determinants, we have tested the ability of these mutant PTHRs to associate with ␤-arrestins by using three different methodological approaches: 1) ability of overexpression of ␤-arrestins to restore the internalization of 125 I-PTH-related protein for the mutant PTHRs; 2) visualization of PTH-mediated trafficking of ␤-arrestin1 and -2 fused to the green fluorescent protein with receptors by confocal microscopy; 3) quantification of ␤-arrestin1-green fluorescent protein translocation by Western blot. Our data reveal that the receptor' cytoplasmic tail contains determinants of ␤-arrestin interaction that are distinct from the phosphorylation sites and are sufficient for transient association of ␤-arrestin2, but stable association requires receptor phosphorylation. Determinants in the receptor's core (Asn-289 and Lys-382) appear to regulate internalization of the receptor/␤-arrestin complex toward early endocytic endosomes during the initial step of endocytosis.Agonist binding to most G protein-coupled receptors (GPCRs) 1 is quickly followed by the internalization of the agonist-receptor complex into endocytic vesicles. The model developed from studies of the ␤ 2 -adrenergic receptor views internalization as a process facilitated by binding of ␤-arrestin proteins to agonist-activated receptors after phosphorylation of the receptors by G protein-coupled receptor kinases (GRKs) (1, 2). Phosphorylation of GPCRs by GRKs is a prerequisite for the mobilization of cytosolic ␤-arrestins. Binding of ␤-arrestins to GRK-phosphorylated receptors results in the physical uncoupling of receptors from their cognate G proteins and terminates agonist-mediated signaling (3, 4). It was shown recently that ␤-arrestins bind clathrin, a major component of the clathrinbased endocytic machinery, with high affinity and serve as an adaptor that targets activated and phosphorylated receptors to clathrin-coated pits (5-7). In the case of the ␤ 2 -adrenergic receptor, receptor internalization is the consequence of the formation of a complex between ␤-arrestin2, the clathrin adaptor protein AP2, clathrin, and the activated receptor (8). Internalization has at least two outcomes: directing the receptor to a compartment where the phosphates are removed, allowing resensitization, and movement of the r...

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Section: Discussionmentioning

confidence: 99%

Section: Agonist Binding To Most G Protein-coupled Receptorsmentioning

confidence: 99%

Internalization Determinants of the Parathyroid Hormone Receptor Differentially Regulate β-Arrestin/Receptor Association

Vilardaga

Krasel

Chauvin

et al. 2002

Journal of Biological Chemistry

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“…Early structural studies conducted on ␤-arr1 and arrestin, found exclusively in visual tissues, reported the existence of oligomers in crystals, indicating that this family of proteins may have the propensity to form oligomers (13)(14)(15). However, the existence of constitutive oligomers in living cells at physiological concentrations was only recently confirmed (16).…”

mentioning

confidence: 99%

β-arrestin 2 oligomerization controls the Mdm2-dependent inhibition of p53

Boularan

Scott

Bourougaa

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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␤-arrestins (␤-arrs), two ubiquitous proteins involved in serpentine heptahelical receptor regulation and signaling, form constitutive homo-and heterooligomers stabilized by inositol 1,2,3,4,5,6-hexakisphosphate (IP6). Monomeric ␤-arrs are believed to interact with receptors after agonist activation, and therefore, ␤-arr oligomers have been proposed to represent a resting biologically inactive state. In contrast to this, we report here that the interaction with and subsequent titration out of the nucleus of the protooncogene Mdm2 specifically require ␤-arr2 oligomers together with the previously characterized nucleocytoplasmic shuttling of ␤-arr2. Mutation of the IP6-binding sites impair oligomerization, reduce interaction with Mdm2, and inhibit p53-dependent antiproliferative effects of ␤-arr2, whereas the competence for receptor regulation and signaling is maintained. These observations suggest that the intracellular concentration of ␤-arr2 oligomers might control cell survival and proliferation. bioluminescence resonance energy transfer ͉ FRET ͉ nucleocytoplasmic shuttling ͉ ubiquitination

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“…Mechanisms for the binding of arrestins to receptors have been described based largely on biochemical, biophysical, structural, and mutational studies of visual arrestin (8). This protein exhibits great selectivity for binding to light-activated, phosphorylated rhodopsin, with binding resulting in signal termination (9).…”

mentioning

confidence: 99%

“…This protein exhibits great selectivity for binding to light-activated, phosphorylated rhodopsin, with binding resulting in signal termination (9). With the recent x-ray crystallographic determination of visual arrestin, a much more precise understanding of the functional properties of arrestins has come to light (8). The structure of visual arrestin consists of two domains with a highly polar core comprised mostly of amino-terminal domain residues.…”

mentioning

confidence: 99%

Arrestin Binding to the G Protein-coupled N-Formyl Peptide Receptor Is Regulated by the Conserved “DRY” Sequence

Bennett

Maestas

Prossnitz³

2000

Journal of Biological Chemistry

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Following activation by ligand, the N-formyl peptide receptor (FPR) undergoes processing events initiated by phosphorylation that lead to receptor desensitization and internalization. Our previous results have shown that FPR internalization can occur in the absence of receptor desensitization, suggesting that FPR desensitization and internalization are controlled by distinct mechanisms. More recently, we have provided evidence that internalization of the FPR occurs via a mechanism that is independent of the actions of arrestin, dynamin, and clathrin. In the present report, we demonstrate that stimulation of the FPR with agonist leads to a significant translocation of arrestin-2 from the cytosol to the membrane. Fluorescence microscopy revealed that the translocated arrestin-2 is highly colocalized with the ligand-bound FPR. A D71A mutant FPR, which does not undergo activation or phosphorylation in response to ligand, did not colocalize with arrestin-2. Surprisingly, an R123G mutant FPR, which does not bind G protein but does become phosphorylated and subsequently internalized, also did not bind arrestin. These results indicate that arrestin binding is not required for FPR internalization and demonstrate for the first time that a common motif, the conserved "DRY" domain of G protein-coupled receptors, is essential for phosphorylation-dependent arrestin binding, as well as G protein activation.

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A Model for Arrestin’s Regulation: The 2.8 Å Crystal Structure of Visual Arrestin

Cited by 395 publications

References 59 publications

Internalization Determinants of the Parathyroid Hormone Receptor Differentially Regulate β-Arrestin/Receptor Association

Internalization Determinants of the Parathyroid Hormone Receptor Differentially Regulate β-Arrestin/Receptor Association

β-arrestin 2 oligomerization controls the Mdm2-dependent inhibition of p53

Arrestin Binding to the G Protein-coupled N-Formyl Peptide Receptor Is Regulated by the Conserved “DRY” Sequence

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