ARBK2_HUMAN
ID ARBK2_HUMAN Reviewed; 688 AA.
AC P35626; Q9UGW9;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 2.
DT 03-AUG-2022, entry version 204.
DE RecName: Full=Beta-adrenergic receptor kinase 2;
DE Short=Beta-ARK-2;
DE EC=2.7.11.15 {ECO:0000250|UniProtKB:P26819};
DE AltName: Full=G-protein-coupled receptor kinase 3 {ECO:0000312|MIM:109636};
GN Name=GRK3 {ECO:0000312|MIM:109636}; Synonyms=ADRBK2, BARK2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=8427589; DOI=10.1006/bbrc.1993.1072;
RA Parruti G., Ambrosini G., Sallese M., de Blasi A.;
RT "Molecular cloning, functional expression and mRNA analysis of human beta-
RT adrenergic receptor kinase 2.";
RL Biochem. Biophys. Res. Commun. 190:475-481(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M.,
RA Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C.,
RA Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E.,
RA Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C.,
RA Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G.,
RA Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V.,
RA Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M.,
RA Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E.,
RA Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F.,
RA Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M.,
RA Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A.,
RA Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D.,
RA Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y.,
RA Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S.,
RA Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E.,
RA Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A.,
RA Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L.,
RA Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P.,
RA Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P.,
RA Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q.,
RA Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J.,
RA Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J.,
RA Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D.,
RA Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T.,
RA Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P.,
RA Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K.,
RA Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L.,
RA McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J.,
RA Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E.,
RA Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P.,
RA Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y.,
RA Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [3]
RP UBIQUITINATION.
RX PubMed=20596523; DOI=10.1371/journal.pone.0011332;
RA Del Rincon S.V., Rogers J., Widschwendter M., Sun D., Sieburg H.B.,
RA Spruck C.;
RT "Development and validation of a method for profiling post-translational
RT modification activities using protein microarrays.";
RL PLoS ONE 5:E11332-E11332(2010).
RN [4]
RP VARIANTS [LARGE SCALE ANALYSIS] SER-50; SER-60 AND LYS-104.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Specifically phosphorylates the agonist-occupied form of the
CC beta-adrenergic and closely related receptors.
CC {ECO:0000250|UniProtKB:P26819}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[beta-adrenergic receptor] + ATP = [beta-adrenergic receptor]-
CC phosphate + ADP + H(+); Xref=Rhea:RHEA:19429, Rhea:RHEA-COMP:11222,
CC Rhea:RHEA-COMP:11223, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43176, ChEBI:CHEBI:68546, ChEBI:CHEBI:456216;
CC EC=2.7.11.15; Evidence={ECO:0000250|UniProtKB:P26819};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19430;
CC Evidence={ECO:0000250|UniProtKB:P26819};
CC -!- SUBUNIT: Interacts with GIT1. {ECO:0000250|UniProtKB:P26819}.
CC -!- INTERACTION:
CC P35626; P25098: GRK2; NbExp=2; IntAct=EBI-2875868, EBI-3904795;
CC -!- SUBCELLULAR LOCATION: Postsynapse {ECO:0000250|UniProtKB:P26819}.
CC Presynapse {ECO:0000250|UniProtKB:P26819}.
CC -!- PTM: Ubiquitinated. {ECO:0000269|PubMed:20596523}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr
CC protein kinase family. GPRK subfamily. {ECO:0000305}.
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DR EMBL; X69117; CAA48870.1; -; mRNA.
DR EMBL; AL022329; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS13832.1; -.
DR PIR; JC1469; JC1469.
DR RefSeq; NP_005151.2; NM_005160.3.
DR AlphaFoldDB; P35626; -.
DR SMR; P35626; -.
DR BioGRID; 106666; 13.
DR IntAct; P35626; 6.
DR STRING; 9606.ENSP00000317578; -.
DR BindingDB; P35626; -.
DR ChEMBL; CHEMBL1075166; -.
DR DrugBank; DB00171; ATP.
DR GuidetoPHARMACOLOGY; 1467; -.
DR GlyConnect; 1034; 1 N-Linked glycan (1 site).
DR GlyGen; P35626; 1 site, 1 N-linked glycan (1 site).
DR iPTMnet; P35626; -.
DR PhosphoSitePlus; P35626; -.
DR BioMuta; GRK3; -.
DR DMDM; 116241253; -.
DR EPD; P35626; -.
DR jPOST; P35626; -.
DR MassIVE; P35626; -.
DR MaxQB; P35626; -.
DR PaxDb; P35626; -.
DR PeptideAtlas; P35626; -.
DR PRIDE; P35626; -.
DR ProteomicsDB; 55118; -.
DR Antibodypedia; 234; 431 antibodies from 34 providers.
DR DNASU; 157; -.
DR Ensembl; ENST00000324198.11; ENSP00000317578.4; ENSG00000100077.16.
DR GeneID; 157; -.
DR KEGG; hsa:157; -.
DR MANE-Select; ENST00000324198.11; ENSP00000317578.4; NM_005160.4; NP_005151.2.
DR UCSC; uc003abx.5; human.
DR CTD; 157; -.
DR DisGeNET; 157; -.
DR GeneCards; GRK3; -.
DR HGNC; HGNC:290; GRK3.
DR HPA; ENSG00000100077; Tissue enhanced (adipose).
DR MIM; 109636; gene.
DR neXtProt; NX_P35626; -.
DR OpenTargets; ENSG00000100077; -.
DR PharmGKB; PA41; -.
DR VEuPathDB; HostDB:ENSG00000100077; -.
DR eggNOG; KOG0986; Eukaryota.
DR GeneTree; ENSGT00940000157699; -.
DR InParanoid; P35626; -.
DR OMA; KHFSLTI; -.
DR OrthoDB; 1083437at2759; -.
DR PhylomeDB; P35626; -.
DR TreeFam; TF313940; -.
DR BRENDA; 2.7.11.15; 2681.
DR PathwayCommons; P35626; -.
DR Reactome; R-HSA-418555; G alpha (s) signalling events.
DR Reactome; R-HSA-8856825; Cargo recognition for clathrin-mediated endocytosis.
DR SignaLink; P35626; -.
DR SIGNOR; P35626; -.
DR BioGRID-ORCS; 157; 11 hits in 1109 CRISPR screens.
DR ChiTaRS; GRK3; human.
DR GeneWiki; Beta_adrenergic_receptor_kinase-2; -.
DR GenomeRNAi; 157; -.
DR Pharos; P35626; Tchem.
DR PRO; PR:P35626; -.
DR Proteomes; UP000005640; Chromosome 22.
DR RNAct; P35626; protein.
DR Bgee; ENSG00000100077; Expressed in Brodmann (1909) area 23 and 184 other tissues.
DR ExpressionAtlas; P35626; baseline and differential.
DR Genevisible; P35626; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0042995; C:cell projection; IEA:UniProtKB-KW.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0098794; C:postsynapse; IEA:UniProtKB-SubCell.
DR GO; GO:0098793; C:presynapse; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0047696; F:beta-adrenergic receptor kinase activity; TAS:Reactome.
DR GO; GO:0001664; F:G protein-coupled receptor binding; IBA:GO_Central.
DR GO; GO:0004703; F:G protein-coupled receptor kinase activity; IBA:GO_Central.
DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central.
DR GO; GO:0002029; P:desensitization of G protein-coupled receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0006468; P:protein phosphorylation; IBA:GO_Central.
DR GO; GO:0031623; P:receptor internalization; IDA:UniProtKB.
DR GO; GO:0009966; P:regulation of signal transduction; IBA:GO_Central.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR Gene3D; 1.10.167.10; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR000239; GPCR_kinase.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR016137; RGS.
DR InterPro; IPR036305; RGS_sf.
DR InterPro; IPR044926; RGS_subdomain_2.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF00069; Pkinase; 1.
DR Pfam; PF00615; RGS; 1.
DR PRINTS; PR00717; GPCRKINASE.
DR SMART; SM00233; PH; 1.
DR SMART; SM00315; RGS; 1.
DR SMART; SM00133; S_TK_X; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF48097; SSF48097; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51285; AGC_KINASE_CTER; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
DR PROSITE; PS50132; RGS; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell projection; Kinase; Nucleotide-binding;
KW Reference proteome; Serine/threonine-protein kinase; Synapse; Transferase;
KW Ubl conjugation.
FT CHAIN 1..688
FT /note="Beta-adrenergic receptor kinase 2"
FT /id="PRO_0000085632"
FT DOMAIN 54..175
FT /note="RGS"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00171"
FT DOMAIN 191..453
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 454..521
FT /note="AGC-kinase C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT DOMAIN 558..652
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT REGION 1..190
FT /note="N-terminal"
FT REGION 669..688
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 317
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 197..205
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 220
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT VARIANT 50
FT /note="R -> S (in dbSNP:rs55700971)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040380"
FT VARIANT 60
FT /note="N -> S (in dbSNP:rs55740593)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040381"
FT VARIANT 104
FT /note="R -> K (in a lung bronchoalveolar carcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_040382"
FT VARIANT 409
FT /note="V -> M (in dbSNP:rs2272859)"
FT /id="VAR_028005"
FT CONFLICT 308
FT /note="M -> V (in Ref. 1; CAA48870)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 688 AA; 79710 MW; 50844236A01C1423 CRC64;
MADLEAVLAD VSYLMAMEKS KATPAARASK RIVLPEPSIR SVMQKYLAER NEITFDKIFN
QKIGFLLFKD FCLNEINEAV PQVKFYEEIK EYEKLDNEED RLCRSRQIYD AYIMKELLSC
SHPFSKQAVE HVQSHLSKKQ VTSTLFQPYI EEICESLRGD IFQKFMESDK FTRFCQWKNV
ELNIHLTMNE FSVHRIIGRG GFGEVYGCRK ADTGKMYAMK CLDKKRIKMK QGETLALNER
IMLSLVSTGD CPFIVCMTYA FHTPDKLCFI LDLMNGGDLH YHLSQHGVFS EKEMRFYATE
IILGLEHMHN RFVVYRDLKP ANILLDEHGH ARISDLGLAC DFSKKKPHAS VGTHGYMAPE
VLQKGTAYDS SADWFSLGCM LFKLLRGHSP FRQHKTKDKH EIDRMTLTVN VELPDTFSPE
LKSLLEGLLQ RDVSKRLGCH GGGSQEVKEH SFFKGVDWQH VYLQKYPPPL IPPRGEVNAA
DAFDIGSFDE EDTKGIKLLD CDQELYKNFP LVISERWQQE VTETVYEAVN ADTDKIEARK
RAKNKQLGHE EDYALGKDCI MHGYMLKLGN PFLTQWQRRY FYLFPNRLEW RGEGESRQNL
LTMEQILSVE ETQIKDKKCI LFRIKGGKQF VLQCESDPEF VQWKKELNET FKEAQRLLRR
APKFLNKPRS GTVELPKPSL CHRNSNGL
