Alternative titles; symbols
HGNC Approved Gene Symbol: ARRB1
Cytogenetic location: 11q13.4 Genomic coordinates (GRCh38): 11:75,260,122-75,351,661 (from NCBI)
Homologous or agonist-specific desensitization is a widespread process that causes specific dampening of cellular responses to stimuli such as hormones, neurotransmitters, or sensory signals. It is defined by a loss of responsiveness of receptors that have been continuously or repeatedly stimulated, while the responses of other receptors remain intact. Homologous desensitization of beta-adrenergic receptors is thought to be mediated by a specific kinase, called beta-adrenergic receptor kinase (BARK, or ADRBK1; 109635). A cofactor is required for this kinase to inhibit receptor function. Lohse et al. (1990) cloned the cDNA for this cofactor and found that it encodes a 418-amino acid protein homologous to the retinal protein arrestin.
Lohse et al. (1990) found that purified beta-arrestin inhibited the signaling function of BARK-phosphorylated beta-adrenergic receptors by more than 75%, but not that of rhodopsin (180380).
Luttrell et al. (1999) showed that stimulation of beta-2 adrenergic receptors (see 109690) resulted in the assembly of a protein complex containing activated SRC (SRC; 190090) and the receptor. They demonstrated that SRC binds to beta-arrestin-1 at its amino terminus. Beta-arrestin-1 mutants, impaired either in SRC binding or in the ability to target receptors to clathrin-coated pits, acted as dominant negative inhibitors of beta-2 adrenergic receptor-mediated activation of the MAP kinases ERK1 (601795) and ERK2 (176948).
Buchanan et al. (2006) found that prostaglandin E2 (PGE2) induced association of PGE2 receptor-4 (PTGER4; 601586), beta-arrestin-1, and Src in a signaling complex that transactivated EGF receptor (EGFR; 131550) and downstream AKT (see AKT1; 164730) signaling. The interaction of beta-arrestin-1 with Src was critical for regulation of human colorectal carcinoma cell migration in vitro, as well as for metastatic spread of disease from spleen to liver in nude mice.
Seven-transmembrane receptor signaling is transduced by second messengers such as diacylglycerol (DAG) generated in response to the heterotrimeric guanine nucleotide-binding protein G(q) (600998) and is terminated by receptor desensitization and degradation of the second messengers. Nelson et al. (2007) showed that beta-arrestins coordinate both processes for the G(q)-coupled M1 muscarinic receptor (CHRM1; 118510). Beta-arrestins physically interact with diacylglycerol kinases (see 125855), enzymes that degrade DAG. Moreover, beta-arrestins are essential for conversion of DAG to phosphatidic acid after agonist stimulation, and this activity requires recruitment of the beta-arrestin-DGK complex to activated 7-transmembrane receptors. The dual function of beta-arrestins, limiting production of diacylglycerol (by receptor desensitization) while enhancing its rate of degradation, is analogous to their ability to recruit adenosine 3-prime,5-prime-monophosphate phosphodiesterases to G(s) (139320)-coupled beta-2-adrenergic receptors (ADRB2; 109690). Thus, Nelson et al. (2007) concluded that beta-arrestins can serve similar regulatory functions for disparate classes of 7-transmembrane receptors through structurally dissimilar enzymes that degrade chemically distinct second messengers.
Kovacs et al. (2008) demonstrated that beta-arrestins mediate the activity-dependent interaction of Smoothened (SMO; 601500) and the kinesin motor protein KIF3A (604683). This multimeric complex localized to primary cilia and was disrupted in cells transfected with beta-arrestin small interfering RNA. Beta-arrestin-1 or beta-arrestin-2 (ARRB2; 107941) depletion prevented the localization of SMO to primary cilia and the SMO-dependent activation of GLI (165220). Kovacs et al. (2008) concluded that their results suggested roles for beta-arrestin in mediating the intracellular transport of a 7-transmembrane receptor to its obligate subcellular location for signaling.
Using immunofluorescence microscopy, Coureuil et al. (2010) demonstrated that Neisseria meningitidis (Nm) colonies at the cell surface of human brain endothelial cells promoted translocation of ARRB1 and ARRB2 to the inner surface of the plasma membrane, facing the bacteria. ARRBs translocated under the colonies served as a scaffolding platform for signaling events elicited by Nm. ADRB2 was the only G protein-coupled receptor expressed in the cell line that played a permissive role in the formation of cortical plaques under colonies and in bacterial crossing of cell monolayers. Coureuil et al. (2010) concluded that the ADRB2/ARRB signaling pathway is required for Nm to promote stable adhesion to brain endothelial cells and subsequent crossing of the blood-brain barrier.
Hara et al. (2011) elucidated a molecular mechanism by which beta-adrenergic catecholamines, acting through both Gs-PKA (see 188830) and beta-arrestin-mediated signaling pathways, trigger DNA damage and suppress p53 (191170) levels respectively, thus synergistically leading to the accumulation of DNA damage. In mice and in human cell lines, ARRB1, activated via beta-2-adrenoreceptors, facilitated AKT (see 164730)-mediated activation of MDM2 (164785) and also promoted MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. Catecholamine-induced DNA damage is abrogated in Arrb1-knockout mice, which showed preserved p53 levels in both thymus, an organ that responds prominently to acute or chronic stress, and in the testes. Hara et al. (2011) concluded that their results highlighted the role of ARRB1 as an E3-ligase adaptor in the nucleus, and revealed how DNA damage may accumulate in response to chronic stress.
Using immunoprecipitation analysis, Puca et al. (2013) showed that human ARRDC1 (619768) interacted directly with ITCH (606409) and that the interaction was mediated by the PPxY motifs of ARRDC1. Simultaneously, ARRDC1 interacted directly with beta-arrestin-1 and beta-arrestin-2 to form a complex that recruited ITCH to NOTCH (NOTCH1; 190198). Through these interactions, ARRDC1 was involved in ITCH-mediated NOTCH ubiquitylation and lysosomal degradation at the same step, but not redundantly, with the beta-arrestins. Moreover, ARRDC1 and the beta-arrestins acted as negative regulators of NOTCH signaling as members of the same complex.
Eichel et al. (2018) demonstrated a distinct and additional mechanism of beta-arrestin activation that does not require stable G protein-coupled receptor (GPCR)-beta-arrestin scaffolding or the GPCR tail. Instead, it occurs through transient engagement of the GPCR core, which destabilizes a conserved interdomain charge network in beta-arrestin. This promotes capture of beta-arrestin at the plasma membrane and its accumulation in clathrin-coated endocytic structures (CCSs) after dissociation from the GPCR, requiring a series of interactions with membrane phosphoinositides and CCS-lattice proteins. Beta-arrestin clustering in CCSs in the absence of the upstream activating GPCR is associated with a beta-arrestin-dependent component of the cellular ERK response. Eichel et al. (2018) concluded that their results delineated a discrete mechanism of cellular beta-arrestin function that is activated catalytically by GPCRs.
Shukla et al. (2013) reported the crystal structure of beta-arrestin-1 in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp) (300538). This peptide had been shown to functionally and conformationally activate beta-arrestin-1. To capture this active conformation, Shukla et al. (2013) used a conformationally selective synthetic antibody fragment (Fab30) that recognizes the phosphopeptide-activated state of beta-arrestin-1. The structure of the beta-arrestin-1-V2Rpp-Fab30 complex shows marked conformational differences in beta-arrestin-1 compared to its inactive conformation. These differences included rotation of the amino- and carboxy-terminal domains relative to each other, and a major reorientation of the 'lariat loop' implicated in maintaining the inactive state of beta-arrestin-1. Shukla et al. (2013) concluded that their results revealed, at high resolution, a receptor-interacting interface on beta-arrestin, and they indicated a potentially general molecular mechanism for activation of these multifunctional signaling and regulatory proteins.
Staus et al. (2020) presented a cryoelectron microscopy structure of beta-arrestin-1 (beta-arr1) in complex with M2 muscarinic receptor (M2R) (CHRM2; 118493) reconstituted in lipid nanodiscs. The M2R-beta-arr1 complex displays a multimodal network of flexible interactions, including binding of the N domain of beta-arr1 to phosphorylated receptor residues and insertion of the finger loop of beta-arr1 into the M2R 7-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric Go protein (GNAO1; 139311) complex. Moreover, the cryoelectron microscopy map revealed that the C-edge of beta-arr1 engages the lipid bilayer. Through atomistic simulations and biophysical, biochemical, and cellular assays, Staus et al. (2020) showed that the C-edge is critical for stable complex formation, beta-arr1 recruitment, receptor internalization, and desensitization of G protein activation. Staus et al. (2020) concluded that their data suggested that the cooperative interactions of beta-arrestin with both the receptor and the phospholipid bilayer contribute to its functional versatility.
Huang et al. (2020) reported a cryoelectron microscopy structure of full-length human neurotensin receptor-1 (NTSR1; 162651) in complex with truncated human beta-arrestin-1 (beta-arr1(delta-CT)). Huang et al. (2020) found that phosphorylation of NTSR1 is critical for the formation of a stable complex with the truncated beta-arrestin form, and identified phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, Huang et al. (2020) observed a phosphatidylinositol-4,5-bisphosphate molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared with a structure of a rhodopsin (180380)-arrestin-1 complex, in this structure arrestin is rotated by approximately 85 degrees relative to the receptor. Huang et al. (2020) concluded that their findings highlighted both conserved aspects and plasticity among arrestin-receptor interactions.
Lee et al. (2020) determined the cryoelectron microscopy structure of the beta-1 adrenergic receptor (ADRB1; 109630)-ARRB1 complex in lipid nanodiscs bound to the biased agonist formoterol, as well as the crystal structure of formoterol-bound ADRB1 coupled to the G-protein-mimetic nanobody Nb80. ARRB1 coupled to ADRB1 in a manner distinct from that of Gs coupling to ADRB2, as the finger loop of ARRB1 occupied a narrower cleft on the intracellular surface and was closer to transmembrane helix H7 of the receptor compared with the C-terminal alpha-5 helix of Gs. The finger loop adopted by ARRB1 was different from that of visual arrestin (ARR3; 301770) coupled to rhodopsin. ADRB1 coupled to ARRB1 showed considerable differences in structure compared with ADRB1 coupled to Nb80, including an inward movement of extracellular loop-3 and the cytoplasmic ends of H5 and H6. Lee et al. (2020) observed weakened interactions between formoterol and 2 serines in H5 at the orthosteric binding site of ADRB1 and found that formoterol had a lower affinity for the ADRB1-ARRB1 complex than for the ADRB1-Gs complex.
By fluorescence in situ hybridization, Calabrese et al. (1994) demonstrated that the ARRB1 gene maps to 11q13, the region where the gene for the functionally related BARK gene is located. By 2-color FISH, Calabrese et al. (1994) directly confirmed the close localization of these 2 genes, showing ARRB1 to be distal to BARK1. Based on the presence of distinguishable yellow and red signals in a number of metaphases analyzed, it was argued that the 2 loci should be about 1 to 2 Mb apart.
By use of gene targeting and blastocyst-mediated transgenesis, Conner et al. (1997) prepared beta-arrestin-1 knockout mice to define the physiologic role of beta-arrestin-1 in the regulation of G protein-coupled receptors such as the beta-adrenergic receptor. Homozygous mutants were structurally normal and had normal life spans. They displayed normal resting cardiovascular parameters but were more sensitive to beta-receptor agonist-stimulated increases in cardiac ejection fraction, consistent with a role for beta-arrestin-1 in beta-adrenergic receptor desensitization. This represents a mechanism for 'fine tuning' the beta-adrenergic receptor response, which may be open to pharmacologic manipulation.
Buchanan, F. G., Gorden, D. L., Matta, P., Shi, Q., Matrisian, L. M., DuBois, R. N. Role of beta-arrestin 1 in the metastatic progression of colorectal cancer. Proc. Nat. Acad. Sci. 103: 1492-1497, 2006. [PubMed: 16432186] [Full Text: https://doi.org/10.1073/pnas.0510562103]
Calabrese, G., Sallese, M., Stornaiuolo, A., Morizio, E., Palka, G., De Blasi, A. Assignment of the beta-arrestin 1 gene (ARRB1) to human chromosome 11q13. Genomics 24: 169-171, 1994. [PubMed: 7896272] [Full Text: https://doi.org/10.1006/geno.1994.1594]
Conner, D. A., Mathier, M. A., Mortensen, R. M., Christe, M., Vatner, S. F., Seidman, C. E., Seidman, J. G. Beta-arrestin-1 knockout mice appear normal but demonstrate altered cardiac responses to beta-adrenergic stimulation. Circulation Res. 81: 1021-1026, 1997. [PubMed: 9400383] [Full Text: https://doi.org/10.1161/01.res.81.6.1021]
Coureuil, M., Lecuyer, H., Scott, M. G. H., Boularan, C., Enslen, H., Soyer, M., Mikaty, G., Bourdoulous, S., Nassif, X., Marullo, S. Meningococcus hijacks a beta-2-adrenoceptor/beta-arrestin pathway to cross brain microvasculature endothelium. Cell 143: 1149-1160, 2010. [PubMed: 21183077] [Full Text: https://doi.org/10.1016/j.cell.2010.11.035]
Eichel, K., Jullie, D., Barsi-Rhyne, B., Latorraca, N. R., Masureel, M., Sibarita, J.-B., Dror, R. O., von Zastrow, M. Catalytic activation of beta-arrestin by GPCRs. Nature 557: 381-386, 2018. [PubMed: 29720660] [Full Text: https://doi.org/10.1038/s41586-018-0079-1]
Hara, M. R., Kovacs, J. J., Whalen, E. J., Rajagopal, S., Strachan, R. T., Grant, W., Towers, A. J., Williams, B., Lam, C. M., Xiao, K., Shenoy, S. K., Gregory, S. G., Ahn, S., Duckett, D. R., Lefkowitz, R. J. A stress response pathway regulates DNA damage through beta-2-adrenoreceptors and beta-arrestin-1. Nature 477: 349-353, 2011. [PubMed: 21857681] [Full Text: https://doi.org/10.1038/nature10368]
Huang, W., Masureel, M., Qu, Q., Janetzko, J., Inoue, A., Kato, H. E., Robertson, M. J., Nguyen, K. C., Glenn, J. S., Skiniotis, G., Kobilka, B. K. Structure of the neurotensin receptor 1 in complex with beta-arrestin 1. Nature 579: 303-308, 2020. [PubMed: 31945771] [Full Text: https://doi.org/10.1038/s41586-020-1953-1]
Kovacs, J. J., Whalen, E. J., Liu, R., Xiao, K., Kim, J., Chen, M., Wang, J., Chen, W., Lefkowitz, R. J. Beta-arrestin-mediated localization of Smoothened to the primary cilium. Science 320: 1777-1781, 2008. [PubMed: 18497258] [Full Text: https://doi.org/10.1126/science.1157983]
Lee, Y., Warne, T., Nehme, R., Pandey, S., Dwivedi-Angihotri, H., Chaturvedi, M., Edwards, P. C., Garcia-Nafria, J., Leslie, A. G. W., Shukla, A. K., Tate, C. G. Molecular basis of beta-arrestin coupling to formoterol-bound beta-1-adrenoceptor. Nature 583: 862-866, 2020. [PubMed: 32555462] [Full Text: https://doi.org/10.1038/s41586-020-2419-1]
Lohse, M. J., Benovic, J. L., Codina, J., Caron, M. G., Lefkowitz, R. J. Beta-arrestin: a protein that regulates beta-adrenergic receptor function. Science 248: 1547-1550, 1990. [PubMed: 2163110] [Full Text: https://doi.org/10.1126/science.2163110]
Luttrell, L. M., Ferguson, S. S. G., Daaka, Y., Miller, W. E., Maudsley, S., Della Rocca, G. J., Lin, F.-T., Kawakatsu, H., Owada, K., Luttrell, D. K., Caron, M. G., Lefkowitz, R. J. Beta-arrestin-dependent formation of beta-2 adrenergic receptor-Src protein kinase complexes. Science 283: 655-661, 1999. [PubMed: 9924018] [Full Text: https://doi.org/10.1126/science.283.5402.655]
Nelson, C. D., Perry, S. J., Regier, D. S., Prescott, S. M., Topham, M. K., Lefkowitz, R. J. Targeting of diacylglycerol degradation to M1 muscarinic receptors by beta-arrestins. Science 315: 663-666, 2007. [PubMed: 17272726] [Full Text: https://doi.org/10.1126/science.1134562]
Puca, L., Chastagner, P., Meas-Yedid, V., Israel, A., Brou, C. Alpha-arrestin 1 (ARRDC1) and beta-arrestins cooperate to mediate Notch degradation in mammals. J. Cell Sci. 126: 4457-4468, 2013. [PubMed: 23886940] [Full Text: https://doi.org/10.1242/jcs.130500]
Shukla, A. K., Manglik, A., Kruse, A. C., Xiao, K., Reis, R. I., Tseng, W.-C., Staus, D. P., Hilger, D., Uysal, S., Huang, L.-Y., Paduch, M., Tripathi-Shukla, P., Koide, A., Koide, S., Weis, W. I., Kossiakoff, A. A., Kobilka, B. K., Lefkowitz, R. J. Structure of active beta-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide. Nature 497: 137-141, 2013. [PubMed: 23604254] [Full Text: https://doi.org/10.1038/nature12120]
Staus, D. P., Hu, H., Robertson, M. J., Kleinhenz, A. L. W., Wingler, L. M., Capel, W. D., Latorraca, N. R., Lefkowitz, R. J., Skiniotis, G. Structure of the M2 muscarinic receptor-beta-arrestin complex in a lipid nanodisc. Nature 579: 297-302, 2020. [PubMed: 31945772] [Full Text: https://doi.org/10.1038/s41586-020-1954-0]