| Structural highlights
Function
ARRB1_HUMAN Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes. During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein; the binding appears to require additional receptor determinants exposed only in the active receptor conformation. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. Two different modes of arrestin-mediated internalization occur. Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Involved in internalization of P2RY4 and UTP-stimulated internalization of P2RY2. Involved in phosphorylation-dependent internalization of OPRD1 ands subsequent recycling. Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). ERK1/2 activated by the beta-arrestin scaffold is largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Recruits c-Src/SRC to ADRB2 resulting in ERK activation. GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). Inhibits ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). Is required for SP-stimulated endocytosis of NK1R and recruits c-Src/SRC to internalized NK1R resulting in ERK1/2 activation, which is required for the antiapoptotic effects of SP. Is involved in proteinase-activated F2RL1-mediated ERK activity. Acts as signaling scaffold for the AKT1 pathway. Is involved in alpha-thrombin-stimulated AKT1 signaling. Is involved in IGF1-stimulated AKT1 signaling leading to increased protection from apoptosis. Involved in activation of the p38 MAPK signaling pathway and in actin bundle formation. Involved in F2RL1-mediated cytoskeletal rearrangement and chemotaxis. Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. Appears to function as signaling scaffold involved in regulation of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. May serve as nuclear messenger for GPCRs. Involved in OPRD1-stimulated transcriptional regulation by translocating to CDKN1B and FOS promoter regions and recruiting EP300 resulting in acetylation of histone H4. Involved in regulation of LEF1 transcriptional activity via interaction with DVL1 and/or DVL2 Also involved in regulation of receptors other than GPCRs. Involved in Toll-like receptor and IL-1 receptor signaling through the interaction with TRAF6 which prevents TRAF6 autoubiquitination and oligomerization required for activation of NF-kappa-B and JUN. Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) (By similarity). Involved in IL8-mediated granule release in neutrophils.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]
Publication Abstract from PubMed
The two non-visual arrestins, arrestin2 and arrestin3, bind hundreds of GPCRs with different phosphorylation patterns, leading to distinct functional outcomes. Structural information on these interactions is available only for very few GPCRs. Here, we have characterized the interactions between the phosphorylated human CC chemokine receptor 5 (CCR5) and arrestin2. We identified several new CCR5 phosphorylation sites necessary for stable arrestin2 complex formation. Structures of arrestin2 in the apo form and complexes with CCR5 C-terminal phosphopeptides, together with NMR, biochemical, and functional assays, revealed three phosphoresidues in a pXpp motif that are essential for arrestin2 binding and activation. The identified motif appears responsible for robust arrestin2 recruitment in many other GPCRs. An analysis of receptor sequences and available structural and functional information provides hints on the molecular basis of arrestin2/arrestin3 isoform specificity. Our findings demonstrate how multi-site phosphorylation controls GPCRâ
arrestin interactions and provide a framework to probe the intricate details of arrestin signaling.
A key GPCR phosphorylation motif discovered in arrestin2â
CCR5 phosphopeptide complexes.,Isaikina P, Petrovic I, Jakob RP, Sarma P, Ranjan A, Baruah M, Panwalkar V, Maier T, Shukla AK, Grzesiek S Mol Cell. 2023 May 23:S1097-2765(23)00326-X. doi: 10.1016/j.molcel.2023.05.002. PMID:37244255[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Braun L, Christophe T, Boulay F. Phosphorylation of key serine residues is required for internalization of the complement 5a (C5a) anaphylatoxin receptor via a beta-arrestin, dynamin, and clathrin-dependent pathway. J Biol Chem. 2003 Feb 7;278(6):4277-85. Epub 2002 Dec 2. PMID:12464600 doi:http://dx.doi.org/10.1074/jbc.M210120200
- ↑ Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Girnita A, Lefkowitz RJ, Larsson O. {beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase. J Biol Chem. 2005 Jul 1;280(26):24412-9. Epub 2005 May 3. PMID:15878855 doi:10.1074/jbc.M501129200
- ↑ Ahn S, Wei H, Garrison TR, Lefkowitz RJ. Reciprocal regulation of angiotensin receptor-activated extracellular signal-regulated kinases by beta-arrestins 1 and 2. J Biol Chem. 2004 Feb 27;279(9):7807-11. Epub 2004 Jan 7. PMID:14711824 doi:http://dx.doi.org/10.1074/jbc.C300443200
- ↑ Kang J, Shi Y, Xiang B, Qu B, Su W, Zhu M, Zhang M, Bao G, Wang F, Zhang X, Yang R, Fan F, Chen X, Pei G, Ma L. A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription. Cell. 2005 Dec 2;123(5):833-47. PMID:16325578 doi:http://dx.doi.org/10.1016/j.cell.2005.09.011
- ↑ Barnes WG, Reiter E, Violin JD, Ren XR, Milligan G, Lefkowitz RJ. beta-Arrestin 1 and Galphaq/11 coordinately activate RhoA and stress fiber formation following receptor stimulation. J Biol Chem. 2005 Mar 4;280(9):8041-50. Epub 2004 Dec 16. PMID:15611106 doi:http://dx.doi.org/10.1074/jbc.M412924200
- ↑ Huttenrauch F, Pollok-Kopp B, Oppermann M. G protein-coupled receptor kinases promote phosphorylation and beta-arrestin-mediated internalization of CCR5 homo- and hetero-oligomers. J Biol Chem. 2005 Nov 11;280(45):37503-15. Epub 2005 Sep 6. PMID:16144840 doi:http://dx.doi.org/10.1074/jbc.M500535200
- ↑ Stalheim L, Ding Y, Gullapalli A, Paing MM, Wolfe BL, Morris DR, Trejo J. Multiple independent functions of arrestins in the regulation of protease-activated receptor-2 signaling and trafficking. Mol Pharmacol. 2005 Jan;67(1):78-87. Epub 2004 Oct 8. PMID:15475570 doi:http://dx.doi.org/10.1124/mol.104.006072
- ↑ Ren XR, Reiter E, Ahn S, Kim J, Chen W, Lefkowitz RJ. Different G protein-coupled receptor kinases govern G protein and beta-arrestin-mediated signaling of V2 vasopressin receptor. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1448-53. Epub 2005 Jan 25. PMID:15671180 doi:http://dx.doi.org/10.1073/pnas.0409534102
- ↑ Shenoy SK, Drake MT, Nelson CD, Houtz DA, Xiao K, Madabushi S, Reiter E, Premont RT, Lichtarge O, Lefkowitz RJ. beta-arrestin-dependent, G protein-independent ERK1/2 activation by the beta2 adrenergic receptor. J Biol Chem. 2006 Jan 13;281(2):1261-73. Epub 2005 Nov 9. PMID:16280323 doi:http://dx.doi.org/10.1074/jbc.M506576200
- ↑ Gesty-Palmer D, Chen M, Reiter E, Ahn S, Nelson CD, Wang S, Eckhardt AE, Cowan CL, Spurney RF, Luttrell LM, Lefkowitz RJ. Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation. J Biol Chem. 2006 Apr 21;281(16):10856-64. Epub 2006 Feb 21. PMID:16492667 doi:http://dx.doi.org/10.1074/jbc.M513380200
- ↑ McLaughlin NJ, Banerjee A, Kelher MR, Gamboni-Robertson F, Hamiel C, Sheppard FR, Moore EE, Silliman CC. Platelet-activating factor-induced clathrin-mediated endocytosis requires beta-arrestin-1 recruitment and activation of the p38 MAPK signalosome at the plasma membrane for actin bundle formation. J Immunol. 2006 Jun 1;176(11):7039-50. PMID:16709866
- ↑ Wang Y, Tang Y, Teng L, Wu Y, Zhao X, Pei G. Association of beta-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol. 2006 Feb;7(2):139-47. Epub 2005 Dec 25. PMID:16378096 doi:10.1038/ni1294
- ↑ Deshpande DA, Theriot BS, Penn RB, Walker JK. Beta-arrestins specifically constrain beta2-adrenergic receptor signaling and function in airway smooth muscle. FASEB J. 2008 Jul;22(7):2134-41. doi: 10.1096/fj.07-102459. Epub 2008 Mar 12. PMID:18337459 doi:http://dx.doi.org/10.1096/fj.07-102459
- ↑ Zhang X, Wang F, Chen X, Chen Y, Ma L. Post-endocytic fates of delta-opioid receptor are regulated by GRK2-mediated receptor phosphorylation and distinct beta-arrestin isoforms. J Neurochem. 2008 Jul;106(2):781-92. doi: 10.1111/j.1471-4159.2008.05431.x. Epub , 2008 Apr 17. PMID:18419762 doi:http://dx.doi.org/10.1111/j.1471-4159.2008.05431.x
- ↑ Garcia Lopez MA, Aguado Martinez A, Lamaze C, Martinez-A C, Fischer T. Inhibition of dynamin prevents CCL2-mediated endocytosis of CCR2 and activation of ERK1/2. Cell Signal. 2009 Dec;21(12):1748-57. Epub 2009 Jul 28. PMID:19643177 doi:http://dx.doi.org/S0898-6568(09)00217-4
- ↑ Cheung R, Malik M, Ravyn V, Tomkowicz B, Ptasznik A, Collman RG. An arrestin-dependent multi-kinase signaling complex mediates MIP-1beta/CCL4 signaling and chemotaxis of primary human macrophages. J Leukoc Biol. 2009 Oct;86(4):833-45. doi: 10.1189/jlb.0908551. Epub 2009 Jul 20. PMID:19620252 doi:http://dx.doi.org/10.1189/jlb.0908551
- ↑ Isaikina P, Petrovic I, Jakob RP, Sarma P, Ranjan A, Baruah M, Panwalkar V, Maier T, Shukla AK, Grzesiek S. A key GPCR phosphorylation motif discovered in arrestin2⋅CCR5 phosphopeptide complexes. Mol Cell. 2023 May 23:S1097-2765(23)00326-X. PMID:37244255 doi:10.1016/j.molcel.2023.05.002
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