ID ARRB1_HUMAN Reviewed; 418 AA. AC P49407; B6V9G8; O75625; O75630; Q2PP20; Q9BTK8; DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot. DT 05-MAR-2002, sequence version 2. DT 14-OCT-2015, entry version 149. DE RecName: Full=Beta-arrestin-1; DE AltName: Full=Arrestin beta-1; GN Name=ARRB1; Synonyms=ARR1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1A AND 1B). RC TISSUE=Peripheral blood; RX PubMed=8486659; RA Parruti G., Peracchia F., Sallese M., Ambrosini G., Masini M., RA Rotilio D., de Blasi A.; RT "Molecular analysis of human beta-arrestin-1: cloning, tissue RT distribution, and regulation of expression. Identification of two RT isoforms generated by alternative splicing."; RL J. Biol. Chem. 268:9753-9761(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1A AND 1B). RC TISSUE=Brain; RA Yu Q.M., Zhou T.H., Cheng Z.J., Ma L., Pei G.; RT "Molecular cloning of two isoforms of human beta-arrestin 1."; RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NHLBI resequencing and genotyping service (RS&G); RL Submitted (DEC-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1B). RC TISSUE=Lung; RA Kaighin V.A., Martin A.L., Aronstam R.S.; RT "Isolation of cDNA coding for Homo sapiens arrestin, beta 1 (ARRB1), RT transcript variant 2."; RL Submitted (OCT-2008) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1A). RC TISSUE=Uterus; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP INTERACTION WITH CCR2 AND ADRBK1. RX PubMed=9501202; DOI=10.1073/pnas.95.6.2985; RA Aragay A.M., Mellado M., Frade J.M., Martin A.M., Jimenez-Sainz M.C., RA Martinez-A C., Mayor F. Jr.; RT "Monocyte chemoattractant protein-1-induced CCR2B receptor RT desensitization mediated by the G protein-coupled receptor kinase 2."; RL Proc. Natl. Acad. Sci. U.S.A. 95:2985-2990(1998). RN [8] RP MUTAGENESIS OF ARG-169. RX PubMed=10066734; DOI=10.1074/jbc.274.11.6831; RA Kovoor A., Celver J., Abdryashitov R.I., Chavkin C., Gurevich V.V.; RT "Targeted construction of phosphorylation-independent beta-arrestin RT mutants with constitutive activity in cells."; RL J. Biol. Chem. 274:6831-6834(1999). RN [9] RP INTERACTION WITH ADRB2, AND SUBCELLULAR LOCATION. RX PubMed=9924018; DOI=10.1126/science.283.5402.655; RA Luttrell L.M., Ferguson S.S.G., Daaka Y., Miller W.E., Maudsley S., RA Della Rocca G.J., Lin F.-T., Kawakatsu H., Owada K., Luttrell D.K., RA Caron M.G., Lefkowitz R.J.; RT "Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src RT protein kinase complexes."; RL Science 283:655-661(1999). RN [10] RP SUBCELLULAR LOCATION, AND ASSOCIATION WITH ANTAGONIST-STIMULATED RP GPCRS. RX PubMed=10748214; DOI=10.1074/jbc.M910348199; RA Oakley R.H., Laporte S.A., Holt J.A., Caron M.G., Barak L.S.; RT "Differential affinities of visual arrestin, beta arrestin1, and beta RT arrestin2 for G protein-coupled receptors delineate two major classes RT of receptors."; RL J. Biol. Chem. 275:17201-17210(2000). RN [11] RP INTERACTION WITH HCK AND CXCR1. RX PubMed=10973280; DOI=10.1038/79767; RA Barlic J., Andrews J.D., Kelvin A.A., Bosinger S.E., DeVries M.E., RA Xu L., Dobransky T., Feldman R.D., Ferguson S.S., Kelvin D.J.; RT "Regulation of tyrosine kinase activation and granule release through RT beta-arrestin by CXCRI."; RL Nat. Immunol. 1:227-233(2000). RN [12] RP FUNCTION IN INTERNALIZATION OF C5AR1, SUBCELLULAR LOCATION, AND RP INTERACTION WITH C5AR1. RX PubMed=12464600; DOI=10.1074/jbc.M210120200; RA Braun L., Christophe T., Boulay F.; RT "Phosphorylation of key serine residues is required for RT internalization of the complement 5a (C5a) anaphylatoxin receptor via RT a beta-arrestin, dynamin, and clathrin-dependent pathway."; RL J. Biol. Chem. 278:4277-4285(2003). RN [13] RP FUNCTION IN UBIQUITINATION OF IGF1R, AND INTERACTION WITH IGF1R AND RP MDM2. RX PubMed=15878855; DOI=10.1074/jbc.M501129200; RA Girnita L., Shenoy S.K., Sehat B., Vasilcanu R., Girnita A., RA Lefkowitz R.J., Larsson O.; RT "{beta}-Arrestin is crucial for ubiquitination and down-regulation of RT the insulin-like growth factor-1 receptor by acting as adaptor for the RT MDM2 E3 ligase."; RL J. Biol. Chem. 280:24412-24419(2005). RN [14] RP FUNCTION IN AGTR1-MEDIATED ERK SIGNALING. RX PubMed=14711824; DOI=10.1074/jbc.C300443200; RA Ahn S., Wei H., Garrison T.R., Lefkowitz R.J.; RT "Reciprocal regulation of angiotensin receptor-activated extracellular RT signal-regulated kinases by beta-arrestins 1 and 2."; RL J. Biol. Chem. 279:7807-7811(2004). RN [15] RP NUCLEAR FUNCTION IN TRANSCRIPTIONAL REGULATION, SUBCELLULAR LOCATION, RP AND INTERACTION WITH CREB1. RX PubMed=16325578; DOI=10.1016/j.cell.2005.09.011; RA Kang J., Shi Y., Xiang B., Qu B., Su W., Zhu M., Zhang M., Bao G., RA Wang F., Zhang X., Yang R., Fan F., Chen X., Pei G., Ma L.; RT "A nuclear function of beta-arrestin1 in GPCR signaling: regulation of RT histone acetylation and gene transcription."; RL Cell 123:833-847(2005). RN [16] RP FUNCTION IN CYTOSKELETAL REARRANGEMENT, AND SUBCELLULAR LOCATION. RX PubMed=15611106; DOI=10.1074/jbc.M412924200; RA Barnes W.G., Reiter E., Violin J.D., Ren X.-R., Milligan G., RA Lefkowitz R.J.; RT "beta-Arrestin 1 and Galphaq/11 coordinately activate RhoA and stress RT fiber formation following receptor stimulation."; RL J. Biol. Chem. 280:8041-8050(2005). RN [17] RP FUNCTION IN IN INTERNALIZATION OF CCR5, AND INTERACTION WITH CCR5. RX PubMed=16144840; DOI=10.1074/jbc.M500535200; RA Huettenrauch F., Pollok-Kopp B., Oppermann M.; RT "G protein-coupled receptor kinases promote phosphorylation and beta- RT arrestin-mediated internalization of CCR5 homo- and hetero- RT oligomers."; RL J. Biol. Chem. 280:37503-37515(2005). RN [18] RP FUNCTION IN F2LR1-MEDIATED ERK SIGNALING, AND SUBCELLULAR LOCATION. RX PubMed=15475570; DOI=10.1124/mol.104.006072; RA Stalheim L., Ding Y., Gullapalli A., Paing M.M., Wolfe B.L., RA Morris D.R., Trejo J.; RT "Multiple independent functions of arrestins in the regulation of RT protease-activated receptor-2 signaling and trafficking."; RL Mol. Pharmacol. 67:78-87(2005). RN [19] RP FUNCTION IN AVPR2-MEDIATED ERK SIGNALING. RX PubMed=15671180; DOI=10.1073/pnas.0409534102; RA Ren X.-R., Reiter E., Ahn S., Kim J., Chen W., Lefkowitz R.J.; RT "Different G protein-coupled receptor kinases govern G protein and RT beta-arrestin-mediated signaling of V2 vasopressin receptor."; RL Proc. Natl. Acad. Sci. U.S.A. 102:1448-1453(2005). RN [20] RP INTERACTION WITH AP2B1, AND MUTAGENESIS OF PHE-388; ASP-390 AND RP ARG-393. RX PubMed=16516836; DOI=10.1016/j.devcel.2006.01.016; RA Edeling M.A., Mishra S.K., Keyel P.A., Steinhauser A.L., Collins B.M., RA Roth R., Heuser J.E., Owen D.J., Traub L.M.; RT "Molecular switches involving the AP-2 beta2 appendage regulate RT endocytic cargo selection and clathrin coat assembly."; RL Dev. Cell 10:329-342(2006). RN [21] RP FUNCTION IN ADRB2-MEDIATED ERK SIGNALING, AND SUBCELLULAR LOCATION. RX PubMed=16280323; DOI=10.1074/jbc.M506576200; RA Shenoy S.K., Drake M.T., Nelson C.D., Houtz D.A., Xiao K., RA Madabushi S., Reiter E., Premont R.T., Lichtarge O., Lefkowitz R.J.; RT "beta-arrestin-dependent, G protein-independent ERK1/2 activation by RT the beta2 adrenergic receptor."; RL J. Biol. Chem. 281:1261-1273(2006). RN [22] RP FUNCTION IN PTH1R-MEDIATED ERK SIGNALING. RX PubMed=16492667; DOI=10.1074/jbc.M513380200; RA Gesty-Palmer D., Chen M., Reiter E., Ahn S., Nelson C.D., Wang S., RA Eckhardt A.E., Cowan C.L., Spurney R.F., Luttrell L.M., RA Lefkowitz R.J.; RT "Distinct beta-arrestin- and G protein-dependent pathways for RT parathyroid hormone receptor-stimulated ERK1/2 activation."; RL J. Biol. Chem. 281:10856-10864(2006). RN [23] RP FUNCTION IN INTERNALIZATION OF PTAFR, FUNCTION IN THE P38 MAPK RP SIGNALING PATHWAY, FUNCTION IN ACTIN BUNDLE FORMATION, SUBCELLULAR RP LOCATION, AND INTERACTION WITH PTAFR AND MAP2K3. RX PubMed=16709866; DOI=10.4049/jimmunol.176.11.7039; RA McLaughlin N.J., Banerjee A., Kelher M.R., Gamboni-Robertson F., RA Hamiel C., Sheppard F.R., Moore E.E., Silliman C.C.; RT "Platelet-activating factor-induced clathrin-mediated endocytosis RT requires beta-arrestin-1 recruitment and activation of the p38 MAPK RT signalosome at the plasma membrane for actin bundle formation."; RL J. Immunol. 176:7039-7050(2006). RN [24] RP FUNCTION IN TLR/IL-1 RECEPTOR SIGNALING, AND INTERACTION WITH TRAF6. RX PubMed=16378096; DOI=10.1038/ni1294; RA Wang Y., Tang Y., Teng L., Wu Y., Zhao X., Pei G.; RT "Association of beta-arrestin and TRAF6 negatively regulates Toll-like RT receptor-interleukin 1 receptor signaling."; RL Nat. Immunol. 7:139-147(2006). RN [25] RP INTERACTION WITH GPR143. RX PubMed=16524428; DOI=10.1111/j.1600-0749.2006.00292.x; RA Innamorati G., Piccirillo R., Bagnato P., Palmisano I., RA Schiaffino M.V.; RT "The melanosomal/lysosomal protein OA1 has properties of a G protein- RT coupled receptor."; RL Pigment Cell Res. 19:125-135(2006). RN [26] RP INTERACTION WITH AP2B1. RX PubMed=17456551; DOI=10.1242/jcs.03444; RA Fessart D., Simaan M., Zimmerman B., Comeau J., Hamdan F.F., RA Wiseman P.W., Bouvier M., Laporte S.A.; RT "Src-dependent phosphorylation of beta2-adaptin dissociates the beta- RT arrestin-AP-2 complex."; RL J. Cell Sci. 120:1723-1732(2007). RN [27] RP FUNCTION IN BETA-ADRENERGIC RECEPTOR REGULATION. RX PubMed=18337459; DOI=10.1096/fj.07-102459; RA Deshpande D.A., Theriot B.S., Penn R.B., Walker J.K.; RT "Beta-arrestins specifically constrain beta2-adrenergic receptor RT signaling and function in airway smooth muscle."; RL FASEB J. 22:2134-2141(2008). RN [28] RP FUNCTION IN INTERNALIZATION OF OPRD1. RX PubMed=18419762; DOI=10.1111/j.1471-4159.2008.05431.x; RA Zhang X., Wang F., Chen X., Chen Y., Ma L.; RT "Post-endocytic fates of delta-opioid receptor are regulated by GRK2- RT mediated receptor phosphorylation and distinct beta-arrestin RT isoforms."; RL J. Neurochem. 106:781-792(2008). RN [29] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., RA Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in RT a refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [30] RP FUNCTION IN INTERNALIZATION OF CCR2. RX PubMed=19643177; DOI=10.1016/j.cellsig.2009.07.010; RA Garcia Lopez M.A., Aguado Martinez A., Lamaze C., Martinez-Alonso C., RA Fischer T.; RT "Inhibition of dynamin prevents CCL2-mediated endocytosis of CCR2 and RT activation of ERK1/2."; RL Cell. Signal. 21:1748-1757(2009). RN [31] RP PHOSPHORYLATION AT SER-412. RX PubMed=19661922; DOI=10.1038/emboj.2009.215; RA Barthet G., Carrat G., Cassier E., Barker B., Gaven F., Pillot M., RA Framery B., Pellissier L.P., Augier J., Kang D.S., Claeysen S., RA Reiter E., Baneres J.L., Benovic J.L., Marin P., Bockaert J., RA Dumuis A.; RT "Beta-arrestin1 phosphorylation by GRK5 regulates G protein- RT independent 5-HT4 receptor signalling."; RL EMBO J. 28:2706-2718(2009). RN [32] RP INTERACTION WITH MAP2K4/MKK4. RX PubMed=19782076; DOI=10.1016/j.febslet.2009.09.035; RA Li X., MacLeod R., Dunlop A.J., Edwards H.V., Advant N., Gibson L.C., RA Devine N.M., Brown K.M., Adams D.R., Houslay M.D., Baillie G.S.; RT "A scanning peptide array approach uncovers association sites within RT the JNK/beta arrestin signalling complex."; RL FEBS Lett. 583:3310-3316(2009). RN [33] RP FUNCTION IN MIP-1-BETA-STIMULATED CHEMOTAXIS. RX PubMed=19620252; DOI=10.1189/jlb.0908551; RA Cheung R., Malik M., Ravyn V., Tomkowicz B., Ptasznik A., RA Collman R.G.; RT "An arrestin-dependent multi-kinase signaling complex mediates MIP- RT 1beta/CCL4 signaling and chemotaxis of primary human macrophages."; RL J. Leukoc. Biol. 86:833-845(2009). RN [34] RP UBIQUITINATION, DEUBIQUITINATION BY USP33, AND INTERACTION WITH USP33. RX PubMed=19363159; DOI=10.1073/pnas.0901083106; RA Shenoy S.K., Modi A.S., Shukla A.K., Xiao K., Berthouze M., Ahn S., RA Wilkinson K.D., Miller W.E., Lefkowitz R.J.; RT "Beta-arrestin-dependent signaling and trafficking of 7-transmembrane RT receptors is reciprocally regulated by the deubiquitinase USP33 and RT the E3 ligase Mdm2."; RL Proc. Natl. Acad. Sci. U.S.A. 106:6650-6655(2009). RN [35] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-412, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., RA Mann M.; RT "Quantitative phosphoproteomics reveals widespread full RT phosphorylation site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [36] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [37] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-412, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., RA Blagoev B.; RT "System-wide temporal characterization of the proteome and RT phosphoproteome of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [38] RP FUNCTION, AND INTERACTION WITH ACKR3. RX PubMed=22457824; DOI=10.1371/journal.pone.0034192; RA Canals M., Scholten D.J., de Munnik S., Han M.K., Smit M.J., Leurs R.; RT "Ubiquitination of CXCR7 controls receptor trafficking."; RL PLoS ONE 7:E34192-E34192(2012). RN [39] RP FUNCTION, AND INTERACTION WITH ACKR4. RX PubMed=23341447; DOI=10.1074/jbc.M112.406108; RA Watts A.O., Verkaar F., van der Lee M.M., Timmerman C.A., Kuijer M., RA van Offenbeek J., van Lith L.H., Smit M.J., Leurs R., Zaman G.J., RA Vischer H.F.; RT "Beta-arrestin recruitment and G protein signaling by the atypical RT human chemokine decoy receptor CCX-CKR."; RL J. Biol. Chem. 288:7169-7181(2013). RN [40] RP FUNCTION. RX PubMed=23633677; DOI=10.1126/scisignal.2003627; RA Borroni E.M., Cancellieri C., Vacchini A., Benureau Y., Lagane B., RA Bachelerie F., Arenzana-Seisdedos F., Mizuno K., Mantovani A., RA Bonecchi R., Locati M.; RT "Beta-arrestin-dependent activation of the cofilin pathway is required RT for the scavenging activity of the atypical chemokine receptor D6."; RL Sci. Signal. 6:RA30-RA30(2013). RN [41] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-412, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., RA Wang L., Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human RT liver phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [42] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 383-402 IN COMPLEX WITH RP AP2B1. RX PubMed=16903783; DOI=10.1371/journal.pbio.0040262; RA Schmid E.M., Ford M.G.J., Burtey A., Praefcke G.J.K., Peak-Chew S.-Y., RA Mills I.G., Benmerah A., McMahon H.T.; RT "Role of the AP2 beta-appendage hub in recruiting partners for RT clathrin-coated vesicle assembly."; RL PLoS Biol. 4:E262-E262(2006). CC -!- FUNCTION: Functions in regulating agonist-mediated G-protein CC coupled receptor (GPCR) signaling by mediating both receptor CC desensitization and resensitization processes. During homologous CC desensitization, beta-arrestins bind to the GPRK-phosphorylated CC receptor and sterically preclude its coupling to the cognate G- CC protein; the binding appears to require additional receptor CC determinants exposed only in the active receptor conformation. The CC beta-arrestins target many receptors for internalization by acting CC as endocytic adapters (CLASPs, clathrin-associated sorting CC proteins) and recruiting the GPRCs to the adapter protein 2 CC complex 2 (AP-2) in clathrin-coated pits (CCPs). However, the CC extent of beta-arrestin involvement appears to vary significantly CC depending on the receptor, agonist and cell type. Internalized CC arrestin-receptor complexes traffic to intracellular endosomes, CC where they remain uncoupled from G-proteins. Two different modes CC of arrestin-mediated internalization occur. Class A receptors, CC like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta- CC arrestin at or near the plasma membrane and undergo rapid CC recycling. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and CC TACR1 internalize as a complex with arrestin and traffic with it CC to endosomal vesicles, presumably as desensitized receptors, for CC extended periods of time. Receptor resensitization then requires CC that receptor-bound arrestin is removed so that the receptor can CC be dephosphorylated and returned to the plasma membrane. Involved CC in internalization of P2RY4 and UTP-stimulated internalization of CC P2RY2. Involved in phosphorylation-dependent internalization of CC OPRD1 ands subsequent recycling. Involved in the degradation of CC cAMP by recruiting cAMP phosphodiesterases to ligand-activated CC receptors. Beta-arrestins function as multivalent adapter proteins CC that can switch the GPCR from a G-protein signaling mode that CC transmits short-lived signals from the plasma membrane via small CC molecule second messengers and ion channels to a beta-arrestin CC signaling mode that transmits a distinct set of signals that are CC initiated as the receptor internalizes and transits the CC intracellular compartment. Acts as signaling scaffold for MAPK CC pathways such as MAPK1/3 (ERK1/2). ERK1/2 activated by the beta- CC arrestin scaffold is largely excluded from the nucleus and CC confined to cytoplasmic locations such as endocytic vesicles, also CC called beta-arrestin signalosomes. Recruits c-Src/SRC to ADRB2 CC resulting in ERK activation. GPCRs for which the beta-arrestin- CC mediated signaling relies on both ARRB1 and ARRB2 (codependent CC regulation) include ADRB2, F2RL1 and PTH1R. For some GPCRs the CC beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 CC and is inhibited by the other respective beta-arrestin form CC (reciprocal regulation). Inhibits ERK1/2 signaling in AGTR1- and CC AVPR2-mediated activation (reciprocal regulation). Is required for CC SP-stimulated endocytosis of NK1R and recruits c-Src/SRC to CC internalized NK1R resulting in ERK1/2 activation, which is CC required for the antiapoptotic effects of SP. Is involved in CC proteinase-activated F2RL1-mediated ERK activity. Acts as CC signaling scaffold for the AKT1 pathway. Is involved in alpha- CC thrombin-stimulated AKT1 signaling. Is involved in IGF1-stimulated CC AKT1 signaling leading to increased protection from apoptosis. CC Involved in activation of the p38 MAPK signaling pathway and in CC actin bundle formation. Involved in F2RL1-mediated cytoskeletal CC rearrangement and chemotaxis. Involved in AGTR1-mediated stress CC fiber formation by acting together with GNAQ to activate RHOA. CC Appears to function as signaling scaffold involved in regulation CC of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in CC attenuation of NF-kappa-B-dependent transcription in response to CC GPCR or cytokine stimulation by interacting with and stabilizing CC CHUK. May serve as nuclear messenger for GPCRs. Involved in OPRD1- CC stimulated transcriptional regulation by translocating to CDKN1B CC and FOS promoter regions and recruiting EP300 resulting in CC acetylation of histone H4. Involved in regulation of LEF1 CC transcriptional activity via interaction with DVL1 and/or DVL2 CC Also involved in regulation of receptors other than GPCRs. CC Involved in Toll-like receptor and IL-1 receptor signaling through CC the interaction with TRAF6 which prevents TRAF6 autoubiquitination CC and oligomerization required for activation of NF-kappa-B and JUN. CC Binds phosphoinositides. Binds inositolhexakisphosphate (InsP6) CC (By similarity). Involved in IL8-mediated granule release in CC neutrophils. Required for atypical chemokine receptor ACKR2- CC induced RAC1-LIMK1-PAK1-dependent phosphorylation of cofilin CC (CFL1) and for the up-regulation of ACKR2 from endosomal CC compartment to cell membrane, increasing its efficiency in CC chemokine uptake and degradation. Involved in the internalization CC of the atypical chemokine receptor ACKR3. {ECO:0000250, CC ECO:0000269|PubMed:12464600, ECO:0000269|PubMed:14711824, CC ECO:0000269|PubMed:15475570, ECO:0000269|PubMed:15611106, CC ECO:0000269|PubMed:15671180, ECO:0000269|PubMed:15878855, CC ECO:0000269|PubMed:16144840, ECO:0000269|PubMed:16280323, CC ECO:0000269|PubMed:16378096, ECO:0000269|PubMed:16492667, CC ECO:0000269|PubMed:16709866, ECO:0000269|PubMed:18337459, CC ECO:0000269|PubMed:18419762, ECO:0000269|PubMed:19620252, CC ECO:0000269|PubMed:19643177, ECO:0000269|PubMed:22457824, CC ECO:0000269|PubMed:23341447, ECO:0000269|PubMed:23633677}. CC -!- SUBUNIT: Monomer. Homodimer. Homooligomer; the self-association is CC mediated by InsP6-binding. Heterooligomer with ARRB2; the CC association is mediated by InsP6-binding. Interacts with GPR143. CC Interacts with ADRB2 (phosphorylated). Interacts with CHRM2 CC (phosphorylated). Interacts with LHCGR. Interacts with CYTH2 and CC CASR. Interacts with AP2B1 (dephosphorylated at 'Tyr-737'); CC phosphorylation of AP2B1 at 'Tyr-737' disrupts the interaction. CC Interacts (dephosphorylated at Ser-412) with CLTC. Interacts with CC CCR2 and ADRBK1. Interacts with CRR5. Interacts with PTAFR CC (phosphorylated on serine residues). Interacts with CLTC and CC MAP2K3. Interacts with CREB1. Interacts with TRAF6. Interacts with CC IGF1R and MDM2. Interacts with C5AR1. Interacts with PDE4D. CC Interacts with SRC (via the SH3 domain and the protein kinase CC domain); the interaction is independent of the phosphorylation CC state of SRC C-terminus. Interacts with TACR1. Interacts with CC RAF1. Interacts with CHUK, IKBKB and MAP3K14. Interacts with DVL1; CC the interaction is enhanced by phosphorylation of DVL1. Interacts CC with DVL2; the interaction is enhanced by phosphorylation of DVL2. CC Interacts with IGF1R. Associates with MAP kinase p38. Part of a CC MAPK signaling complex consisting of TACR1, ARRB1, SRC, MAPK1 CC (activated) and MAPK3 (activated). Part of a MAPK signaling CC complex consisting of F2RL1, ARRB1, RAF1, MAPK1 (activated) and CC MAPK3 (activated) (By similarity). Interacts with MAP2K4/MKK4. CC Interacts with HCK and CXCR1 (phosphorylated). Interacts with CC ACKR3 and ACKR4. {ECO:0000250, ECO:0000269|PubMed:10973280, CC ECO:0000269|PubMed:12464600, ECO:0000269|PubMed:15878855, CC ECO:0000269|PubMed:16144840, ECO:0000269|PubMed:16325578, CC ECO:0000269|PubMed:16378096, ECO:0000269|PubMed:16516836, CC ECO:0000269|PubMed:16524428, ECO:0000269|PubMed:16709866, CC ECO:0000269|PubMed:16903783, ECO:0000269|PubMed:17456551, CC ECO:0000269|PubMed:19363159, ECO:0000269|PubMed:19782076, CC ECO:0000269|PubMed:22457824, ECO:0000269|PubMed:23341447, CC ECO:0000269|PubMed:9501202, ECO:0000269|PubMed:9924018}. CC -!- INTERACTION: CC P62158:CALM3; NbExp=3; IntAct=EBI-743313, EBI-397435; CC P20963:CD247; NbExp=9; IntAct=EBI-743313, EBI-1165705; CC P50148:GNAQ; NbExp=2; IntAct=EBI-743313, EBI-3909604; CC Q5JWF2:GNAS; NbExp=5; IntAct=EBI-743313, EBI-4400880; CC Q14749:GNMT; NbExp=5; IntAct=EBI-743313, EBI-744239; CC P06396:GSN; NbExp=3; IntAct=EBI-743313, EBI-351506; CC Q16665:HIF1A; NbExp=3; IntAct=EBI-743313, EBI-447269; CC P11142:HSPA8; NbExp=4; IntAct=EBI-743313, EBI-351896; CC Q99683:MAP3K5; NbExp=3; IntAct=EBI-743313, EBI-476263; CC P53779:MAPK10; NbExp=2; IntAct=EBI-743313, EBI-713543; CC P45984:MAPK9; NbExp=5; IntAct=EBI-743313, EBI-713568; CC P19338:NCL; NbExp=3; IntAct=EBI-743313, EBI-346967; CC Q14978:NOLC1; NbExp=3; IntAct=EBI-743313, EBI-396155; CC P14618:PKM; NbExp=3; IntAct=EBI-743313, EBI-353408; CC P35813:PPM1A; NbExp=4; IntAct=EBI-743313, EBI-989143; CC O75688:PPM1B; NbExp=4; IntAct=EBI-743313, EBI-1047039; CC Q13523:PRPF4B; NbExp=2; IntAct=EBI-743313, EBI-395940; CC P06702:S100A9; NbExp=2; IntAct=EBI-743313, EBI-1055001; CC Q15208:STK38; NbExp=3; IntAct=EBI-743313, EBI-458376; CC Q13428:TCOF1; NbExp=3; IntAct=EBI-743313, EBI-396105; CC Q7DB77:tir (xeno); NbExp=3; IntAct=EBI-743313, EBI-6480811; CC P27348:YWHAQ; NbExp=3; IntAct=EBI-743313, EBI-359854; CC P25490:YY1; NbExp=4; IntAct=EBI-743313, EBI-765538; CC O95218:ZRANB2; NbExp=4; IntAct=EBI-743313, EBI-1051583; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cell membrane. Membrane, CC clathrin-coated pit {ECO:0000305}. Cell projection, pseudopodium CC {ECO:0000250}. Cytoplasmic vesicle. Note=Translocates to the CC plasma membrane and colocalizes with antagonist-stimulated GPCRs. CC The monomeric form is predominantly located in the nucleus. The CC oligomeric form is located in the cytoplasm. Translocates to the CC nucleus upon stimulation of OPRD1 (By similarity). {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1A; CC IsoId=P49407-1; Sequence=Displayed; CC Name=1B; CC IsoId=P49407-2; Sequence=VSP_000322; CC -!- DOMAIN: The [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif mediates CC interaction the AP-2 complex subunit AP2B1 (By similarity). CC Binding to phosphorylated GPCRs induces a conformationanl change CC that exposes the motif to the surface. {ECO:0000250}. CC -!- DOMAIN: The N-terminus binds InsP6 with low affinity. CC {ECO:0000250}. CC -!- DOMAIN: The C-terminus binds InsP6 with high affinity. CC {ECO:0000250}. CC -!- PTM: Constitutively phosphorylated at Ser-412 in the cytoplasm. At CC the plasma membrane, is rapidly dephosphorylated, a process that CC is required for clathrin binding and ADRB2 endocytosis but not for CC ADRB2 binding and desensitization. Once internalized, is CC rephosphorylated. {ECO:0000269|PubMed:19661922}. CC -!- PTM: The ubiquitination status appears to regulate the formation CC and trafficking of beta-arrestin-GPCR complexes and signaling. CC Ubiquitination appears to occur GPCR-specific. Ubiquitinated by CC MDM2; the ubiquitination is required for rapid internalization of CC ADRB2. Deubiquitinated by USP33; the deubiquitination leads to a CC dissociation of the beta-arrestin-GPCR complex. Stimulation of a CC class A GPCR, such as ADRB2, induces transient ubiquitination and CC subsequently promotes association with USP33. CC {ECO:0000269|PubMed:19363159}. CC -!- SIMILARITY: Belongs to the arrestin family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Arrestin entry; CC URL="https://en.wikipedia.org/wiki/Arrestin"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; L04685; AAA35559.1; -; mRNA. DR EMBL; L04685; AAA35558.1; -; mRNA. DR EMBL; AF084040; AAC33295.1; -; mRNA. DR EMBL; AF084940; AAC34123.1; -; mRNA. DR EMBL; DQ314865; ABC40724.1; -; Genomic_DNA. DR EMBL; FJ348262; ACI96306.1; -; mRNA. DR EMBL; CH471076; EAW74962.1; -; Genomic_DNA. DR EMBL; BC003636; AAH03636.1; -; mRNA. DR CCDS; CCDS31640.1; -. [P49407-2] DR CCDS; CCDS44684.1; -. [P49407-1] DR PIR; B46682; B46682. DR RefSeq; NP_004032.2; NM_004041.4. [P49407-1] DR RefSeq; NP_064647.1; NM_020251.3. [P49407-2] DR UniGene; Hs.503284; -. DR UniGene; Hs.625320; -. DR PDB; 2IV8; X-ray; 2.80 A; P/Q=383-402. DR PDBsum; 2IV8; -. DR ProteinModelPortal; P49407; -. DR SMR; P49407; 5-393. DR BioGrid; 106901; 251. DR DIP; DIP-29979N; -. DR IntAct; P49407; 208. DR MINT; MINT-128176; -. DR STRING; 9606.ENSP00000409581; -. DR BindingDB; P49407; -. DR ChEMBL; CHEMBL1795088; -. DR PhosphoSite; P49407; -. DR BioMuta; ARRB1; -. DR DMDM; 20141238; -. DR OGP; P49407; -. DR MaxQB; P49407; -. DR PaxDb; P49407; -. DR PRIDE; P49407; -. DR DNASU; 408; -. DR Ensembl; ENST00000360025; ENSP00000353124; ENSG00000137486. [P49407-2] DR Ensembl; ENST00000420843; ENSP00000409581; ENSG00000137486. [P49407-1] DR GeneID; 408; -. DR KEGG; hsa:408; -. DR UCSC; uc001owe.2; human. [P49407-1] DR UCSC; uc001owf.2; human. [P49407-2] DR CTD; 408; -. DR GeneCards; ARRB1; -. DR HGNC; HGNC:711; ARRB1. DR HPA; CAB003763; -. DR HPA; CAB034047; -. DR HPA; HPA049318; -. DR MIM; 107940; gene. DR neXtProt; NX_P49407; -. DR PharmGKB; PA59; -. DR eggNOG; NOG302111; -. DR GeneTree; ENSGT00390000013152; -. DR HOGENOM; HOG000231319; -. DR HOVERGEN; HBG002399; -. DR InParanoid; P49407; -. DR KO; K04439; -. DR OMA; EAPIDTN; -. DR OrthoDB; EOG79W954; -. DR PhylomeDB; P49407; -. DR TreeFam; TF314260; -. DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus. DR Reactome; R-HSA-432720; Lysosome Vesicle Biogenesis. DR Reactome; R-HSA-432722; Golgi Associated Vesicle Biogenesis. DR Reactome; R-HSA-456926; Thrombin signalling through proteinase activated receptors (PARs). DR Reactome; R-HSA-5635838; Activation of SMO. DR Reactome; R-HSA-5674135; MAP2K and MAPK activation. DR SignaLink; P49407; -. DR ChiTaRS; ARRB1; human. DR EvolutionaryTrace; P49407; -. DR GeneWiki; Arrestin_beta_1; -. DR GenomeRNAi; 408; -. DR NextBio; 1713; -. DR PRO; PR:P49407; -. DR Proteomes; UP000005640; Chromosome 11. DR Bgee; P49407; -. DR CleanEx; HS_ARRB1; -. DR ExpressionAtlas; P49407; baseline and differential. DR Genevisible; P49407; HS. DR GO; GO:0016323; C:basolateral plasma membrane; IEA:Ensembl. DR GO; GO:0000785; C:chromatin; IDA:BHF-UCL. DR GO; GO:0005905; C:coated pit; IEA:UniProtKB-SubCell. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:UniProtKB. DR GO; GO:0030659; C:cytoplasmic vesicle membrane; TAS:Reactome. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0043197; C:dendritic spine; IEA:Ensembl. DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome. DR GO; GO:0005765; C:lysosomal membrane; TAS:Reactome. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:ProtInc. DR GO; GO:0014069; C:postsynaptic density; IEA:Ensembl. DR GO; GO:0045211; C:postsynaptic membrane; IEA:Ensembl. DR GO; GO:0031143; C:pseudopodium; IEA:UniProtKB-SubCell. DR GO; GO:0031701; F:angiotensin receptor binding; IPI:UniProtKB. DR GO; GO:0043027; F:cysteine-type endopeptidase inhibitor activity involved in apoptotic process; IEA:Ensembl. DR GO; GO:0004857; F:enzyme inhibitor activity; TAS:ProtInc. DR GO; GO:0005096; F:GTPase activator activity; IMP:UniProtKB. DR GO; GO:0005159; F:insulin-like growth factor receptor binding; IPI:UniProtKB. DR GO; GO:0008134; F:transcription factor binding; IPI:UniProtKB. DR GO; GO:0044212; F:transcription regulatory region DNA binding; IMP:BHF-UCL. DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB. DR GO; GO:0000187; P:activation of MAPK activity; IEA:Ensembl. DR GO; GO:0007596; P:blood coagulation; TAS:Reactome. DR GO; GO:0042699; P:follicle-stimulating hormone signaling pathway; IEA:Ensembl. DR GO; GO:0002031; P:G-protein coupled receptor internalization; IMP:UniProtKB. DR GO; GO:0061024; P:membrane organization; TAS:Reactome. DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IEA:Ensembl. DR GO; GO:0034260; P:negative regulation of GTPase activity; IEA:Ensembl. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IDA:UniProtKB. DR GO; GO:0032717; P:negative regulation of interleukin-8 production; IDA:UniProtKB. DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:UniProtKB. DR GO; GO:0031397; P:negative regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0007219; P:Notch signaling pathway; TAS:Reactome. DR GO; GO:0007602; P:phototransduction; IEA:Ensembl. DR GO; GO:0030168; P:platelet activation; TAS:Reactome. DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Ensembl. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0043547; P:positive regulation of GTPase activity; IMP:GOC. DR GO; GO:0035066; P:positive regulation of histone acetylation; IMP:BHF-UCL. DR GO; GO:0090240; P:positive regulation of histone H4 acetylation; IMP:UniProtKB. DR GO; GO:0035774; P:positive regulation of insulin secretion involved in cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IEA:Ensembl. DR GO; GO:0032092; P:positive regulation of protein binding; IEA:Ensembl. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:UniProtKB. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IEA:Ensembl. DR GO; GO:0002092; P:positive regulation of receptor internalization; IMP:UniProtKB. DR GO; GO:0035025; P:positive regulation of Rho protein signal transduction; IMP:UniProtKB. DR GO; GO:0034393; P:positive regulation of smooth muscle cell apoptotic process; IEA:Ensembl. DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IMP:BHF-UCL. DR GO; GO:0006892; P:post-Golgi vesicle-mediated transport; TAS:Reactome. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB. DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW. DR GO; GO:0016567; P:protein ubiquitination; IMP:UniProtKB. DR GO; GO:0043149; P:stress fiber assembly; IMP:UniProtKB. DR GO; GO:0006366; P:transcription from RNA polymerase II promoter; IMP:UniProtKB. DR Gene3D; 2.60.40.640; -; 1. DR Gene3D; 2.60.40.840; -; 1. DR InterPro; IPR000698; Arrestin. DR InterPro; IPR011021; Arrestin-like_N. DR InterPro; IPR014752; Arrestin_C. DR InterPro; IPR011022; Arrestin_C-like. DR InterPro; IPR017864; Arrestin_CS. DR InterPro; IPR014753; Arrestin_N. DR InterPro; IPR014756; Ig_E-set. DR PANTHER; PTHR11792; PTHR11792; 1. DR Pfam; PF02752; Arrestin_C; 1. DR Pfam; PF00339; Arrestin_N; 1. DR PRINTS; PR00309; ARRESTIN. DR SMART; SM01017; Arrestin_C; 1. DR SUPFAM; SSF81296; SSF81296; 2. DR PROSITE; PS00295; ARRESTINS; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cell projection; KW Coated pit; Complete proteome; Cytoplasm; Cytoplasmic vesicle; KW Membrane; Nucleus; Phosphoprotein; Protein transport; KW Reference proteome; Signal transduction inhibitor; Transcription; KW Transcription regulation; Transport; Ubl conjugation. FT CHAIN 1 418 Beta-arrestin-1. FT /FTId=PRO_0000205194. FT REGION 1 163 Interaction with SRC. {ECO:0000250}. FT REGION 45 86 Interaction with CHRM2. {ECO:0000250}. FT REGION 318 418 Interaction with TRAF6. FT MOTIF 385 395 [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif. FT BINDING 250 250 Inositol hexakisphosphate. {ECO:0000250}. FT BINDING 255 255 Inositol hexakisphosphate. {ECO:0000250}. FT BINDING 324 324 Inositol hexakisphosphate. {ECO:0000250}. FT BINDING 326 326 Inositol hexakisphosphate. {ECO:0000250}. FT MOD_RES 47 47 Phosphotyrosine. FT {ECO:0000250|UniProtKB:Q8BWG8}. FT MOD_RES 412 412 Phosphoserine; by GRK5. FT {ECO:0000244|PubMed:20068231, FT ECO:0000244|PubMed:21406692, FT ECO:0000244|PubMed:24275569, FT ECO:0000269|PubMed:19661922}. FT VAR_SEQ 334 341 Missing (in isoform 1B). FT {ECO:0000303|PubMed:8486659, FT ECO:0000303|Ref.2, ECO:0000303|Ref.4}. FT /FTId=VSP_000322. FT MUTAGEN 169 169 R->E: Constitutive active; enables FT phosphorylation-independent binding to FT GPCRs. {ECO:0000269|PubMed:10066734}. FT MUTAGEN 388 388 F->A: Abolishes interaction with AP2B1. FT {ECO:0000269|PubMed:16516836}. FT MUTAGEN 390 390 D->P: Abolishes interaction with AP2B1. FT {ECO:0000269|PubMed:16516836}. FT MUTAGEN 393 393 R->A: Abolishes interaction with AP2B1. FT {ECO:0000269|PubMed:16516836}. FT CONFLICT 146 146 V -> A (in Ref. 1; AAA35559/AAA35558). FT {ECO:0000305}. FT CONFLICT 165 165 R -> G (in Ref. 1; AAA35559/AAA35558). FT {ECO:0000305}. FT CONFLICT 229 229 K -> E (in Ref. 1; AAA35559/AAA35558). FT {ECO:0000305}. FT CONFLICT 329 329 V -> E (in Ref. 2; AAC33295/AAC34123). FT {ECO:0000305}. FT CONFLICT 400 400 K -> E (in Ref. 1; AAA35559/AAA35558). FT {ECO:0000305}. FT CONFLICT 414 414 Q -> R (in Ref. 1; AAA35559/AAA35558). FT {ECO:0000305}. FT CONFLICT 417 417 N -> D (in Ref. 1; AAA35559/AAA35558). FT {ECO:0000305}. FT HELIX 384 394 {ECO:0000244|PDB:2IV8}. SQ SEQUENCE 418 AA; 47066 MW; 0A3C135092338D10 CRC64; MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVDPVDGV VLVDPEYLKE RRVYVTLTCA FRYGREDLDV LGLTFRKDLF VANVQSFPPA PEDKKPLTRL QERLIKKLGE HAYPFTFEIP PNLPCSVTLQ PGPEDTGKAC GVDYEVKAFC AENLEEKIHK RNSVRLVIRK VQYAPERPGP QPTAETTRQF LMSDKPLHLE ASLDKEIYYH GEPISVNVHV TNNTNKTVKK IKISVRQYAD ICLFNTAQYK CPVAMEEADD TVAPSSTFCK VYTLTPFLAN NREKRGLALD GKLKHEDTNL ASSTLLREGA NREILGIIVS YKVKVKLVVS RGGLLGDLAS SDVAVELPFT LMHPKPKEEP PHREVPENET PVDTNLIELD TNDDDIVFED FARQRLKGMK DDKEEEEDGT GSPQLNNR //