ID GRK5_HUMAN Reviewed; 590 AA. AC P34947; D3DRD0; Q5T059; DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1994, sequence version 1. DT 27-MAR-2024, entry version 211. DE RecName: Full=G protein-coupled receptor kinase 5; DE EC=2.7.11.16; DE AltName: Full=G protein-coupled receptor kinase GRK5; GN Name=GRK5; Synonyms=GPRK5; 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], AND TISSUE SPECIFICITY. RX PubMed=7685906; DOI=10.1073/pnas.90.12.5588; RA Kunapuli P., Benovic J.L.; RT "Cloning and expression of GRK5: a member of the G protein-coupled receptor RT kinase family."; RL Proc. Natl. Acad. Sci. U.S.A. 90:5588-5592(1993). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Prostate; 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP INDUCTION. RX PubMed=8381058; DOI=10.1161/01.cir.87.2.454; RA Ungerer M., Bohm M., Elce J.S., Erdmann E., Lohse M.J.; RT "Altered expression of beta-adrenergic receptor kinase and beta 1- RT adrenergic receptors in the failing human heart."; RL Circulation 87:454-463(1993). RN [6] RP PHOSPHORYLATION AT SER-484 AND THR-485, AND MUTAGENESIS OF SER-484 AND RP THR-485. RX PubMed=8144599; DOI=10.1016/s0021-9258(17)34046-2; RA Kunapuli P., Gurevich V.V., Benovic J.L.; RT "Phospholipid-stimulated autophosphorylation activates the G protein- RT coupled receptor kinase GRK5."; RL J. Biol. Chem. 269:10209-10212(1994). RN [7] RP ACTIVITY REGULATION. RX PubMed=9218466; DOI=10.1074/jbc.272.29.18273; RA Pronin A.N., Satpaev D.K., Slepak V.Z., Benovic J.L.; RT "Regulation of G protein-coupled receptor kinases by calmodulin and RT localization of the calmodulin binding domain."; RL J. Biol. Chem. 272:18273-18280(1997). RN [8] RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF LEU-550; LEU-551; LEU-554 AND RP PHE-555. RX PubMed=14976207; DOI=10.1074/jbc.m310738200; RA Thiyagarajan M.M., Stracquatanio R.P., Pronin A.N., Evanko D.S., RA Benovic J.L., Wedegaertner P.B.; RT "A predicted amphipathic helix mediates plasma membrane localization of RT GRK5."; RL J. Biol. Chem. 279:17989-17995(2004). RN [9] RP SUBCELLULAR LOCATION, NUCLEAR LOCALIZATION SIGNAL, AND MUTAGENESIS OF RP ARG-388; LYS-389; LYS-391; LYS-393 AND ARG-394. RX PubMed=15542828; DOI=10.1128/mcb.24.23.10169-10179.2004; RA Johnson L.R., Scott M.G., Pitcher J.A.; RT "G protein-coupled receptor kinase 5 contains a DNA-binding nuclear RT localization sequence."; RL Mol. Cell. Biol. 24:10169-10179(2004). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-484 AND THR-485, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [11] RP FUNCTION IN PHOSPHORYLATION OF ARRB1, AND INTERACTION WITH HTR4. 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., Reiter E., RA Baneres J.L., Benovic J.L., Marin P., Bockaert J., Dumuis A.; RT "Beta-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5- RT HT4 receptor signalling."; RL EMBO J. 28:2706-2718(2009). RN [12] RP FUNCTION IN PHOSPHORYLATION OF LRP6. RX PubMed=19801552; DOI=10.1074/jbc.m109.047456; RA Chen M., Philipp M., Wang J., Premont R.T., Garrison T.R., Caron M.G., RA Lefkowitz R.J., Chen W.; RT "G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt RT pathway."; RL J. Biol. Chem. 284:35040-35048(2009). RN [13] RP FUNCTION IN PHOSPHORYLATION OF TP53, INTERACTION WITH TP53, AND MUTAGENESIS RP OF LYS-215. RX PubMed=20124405; DOI=10.1074/jbc.m109.094243; RA Chen X., Zhu H., Yuan M., Fu J., Zhou Y., Ma L.; RT "G-protein-coupled receptor kinase 5 phosphorylates p53 and inhibits DNA RT damage-induced apoptosis."; RL J. Biol. Chem. 285:12823-12830(2010). RN [14] RP FUNCTION IN PHOSPHORYLATION OF ADRB2, AND AUTOPHOSPHORYLATION. RX PubMed=20038610; DOI=10.1124/mol.109.058115; RA Baameur F., Morgan D.H., Yao H., Tran T.M., Hammitt R.A., Sabui S., RA McMurray J.S., Lichtarge O., Clark R.B.; RT "Role for the regulator of G-protein signaling homology domain of G RT protein-coupled receptor kinases 5 and 6 in beta 2-adrenergic receptor and RT rhodopsin phosphorylation."; RL Mol. Pharmacol. 77:405-415(2010). RN [15] RP FUNCTION IN PHOSPHORYLATION OF ST13, AND INTERACTION WITH ST13. RX PubMed=21728385; DOI=10.1021/bi2005202; RA Barker B.L., Benovic J.L.; RT "G protein-coupled receptor kinase 5 phosphorylation of Hip regulates RT internalization of the chemokine receptor CXCR4."; RL Biochemistry 50:6933-6941(2011). RN [16] RP VARIANTS [LARGE SCALE ANALYSIS] LEU-41; VAL-119; SER-122; MET-129; ILE-141; RP GLU-163 AND HIS-304. 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). RN [17] RP VARIANT LEU-41, CHARACTERIZATION OF VARIANT LEU-41, POLYMORPHISM, AND RP POSSIBLE PROTECTIVE ROLE IN THE PROGRESSION OF HEART FAILURE. RX PubMed=18425130; DOI=10.1038/nm1750; RA Liggett S.B., Cresci S., Kelly R.J., Syed F.M., Matkovich S.J., Hahn H.S., RA Diwan A., Martini J.S., Sparks L., Parekh R.R., Spertus J.A., Koch W.J., RA Kardia S.L., Dorn G.W. II; RT "A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is RT protective in heart failure."; RL Nat. Med. 14:510-517(2008). CC -!- FUNCTION: Serine/threonine kinase that phosphorylates preferentially CC the activated forms of a variety of G-protein-coupled receptors CC (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated CC receptor desensitization, internalization, and signaling events leading CC to their down-regulation. Phosphorylates a variety of GPCRs, including CC adrenergic receptors, muscarinic acetylcholine receptors (more CC specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid CC receptors. In addition to GPCRs, also phosphorylates various CC substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and CC arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein CC independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. CC Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 CC (MEF2) leading to nuclear export of HDAC5 and allowing MEF2-mediated CC transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, CC inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates CC internalization of the chemokine receptor. Phosphorylates rhodopsin CC (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt CC signaling (in vitro). {ECO:0000269|PubMed:19661922, CC ECO:0000269|PubMed:19801552, ECO:0000269|PubMed:20038610, CC ECO:0000269|PubMed:20124405, ECO:0000269|PubMed:21728385}. CC -!- CATALYTIC ACTIVITY: CC Reaction=[G-protein-coupled receptor] + ATP = [G-protein-coupled CC receptor]-phosphate + ADP + H(+); Xref=Rhea:RHEA:12008, Rhea:RHEA- CC COMP:11260, Rhea:RHEA-COMP:11261, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:43176, ChEBI:CHEBI:68546, CC ChEBI:CHEBI:456216; EC=2.7.11.16; CC -!- ACTIVITY REGULATION: Inhibited by calmodulin with an IC(50) of 50 nM. CC Calmodulin inhibits GRK5 association with receptor and phospholipid. CC {ECO:0000269|PubMed:9218466}. CC -!- SUBUNIT: Interacts with ST13 (via the C-terminus 303-319 AA) CC (PubMed:21728385). Interacts with TP53/p53 (PubMed:20124405). Interacts CC with HTR4 (via C-terminus 330-346 AA); this interaction is promoted by CC 5-HT (serotonin) (PubMed:19661922). Interacts with HDAC5 (By CC similarity). Interacts with GIT1 (By similarity). {ECO:0000250, CC ECO:0000250|UniProtKB:Q62833, ECO:0000250|UniProtKB:Q8VEB1, CC ECO:0000269|PubMed:19661922, ECO:0000269|PubMed:20124405, CC ECO:0000269|PubMed:21728385}. CC -!- INTERACTION: CC P34947; P25963: NFKBIA; NbExp=2; IntAct=EBI-7149314, EBI-307386; CC P34947; P97288: Htr4; Xeno; NbExp=8; IntAct=EBI-7149314, EBI-7149283; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cell membrane; Peripheral CC membrane protein. Note=Predominantly localized at the plasma membrane; CC targeted to the cell surface through the interaction with CC phospholipids. Nucleus localization is regulated in a GPCR and CC Ca(2+)/calmodulin-dependent fashion. CC -!- TISSUE SPECIFICITY: Highest levels in heart, placenta, lung > skeletal CC muscle > brain, liver, pancreas > kidney. {ECO:0000269|PubMed:7685906}. CC -!- INDUCTION: Overexpressed during heart failure. CC {ECO:0000269|PubMed:8381058}. CC -!- PTM: Autophosphorylated. Autophosphorylation may play a critical role CC in the regulation of GRK5 kinase activity. CC {ECO:0000269|PubMed:8144599}. CC -!- POLYMORPHISM: Variant Leu-41 variant is rare in European-Americans CC individuals but common in African-Americans individuals (40% of the CC African-American individuals studied carry at least one allele). CC Variant leu-41 is associated with decreased mortality in African- CC Americans with heart failure or cardiac ischemia. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr CC protein kinase family. GPRK subfamily. {ECO:0000305}. 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; L15388; AAA58620.1; -; mRNA. DR EMBL; AL355273; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL355861; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL583824; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471066; EAW49394.1; -; Genomic_DNA. DR EMBL; CH471066; EAW49395.1; -; Genomic_DNA. DR EMBL; BC064506; AAH64506.1; -; mRNA. DR CCDS; CCDS7612.1; -. DR PIR; A48277; A48277. DR PIR; B48682; B48682. DR RefSeq; NP_005299.1; NM_005308.2. DR PDB; 4TNB; X-ray; 2.11 A; A=1-590. DR PDB; 4TND; X-ray; 1.80 A; A=1-590. DR PDB; 6PJX; X-ray; 1.96 A; A=1-590. DR PDBsum; 4TNB; -. DR PDBsum; 4TND; -. DR PDBsum; 6PJX; -. DR AlphaFoldDB; P34947; -. DR SMR; P34947; -. DR BioGRID; 109127; 176. DR DIP; DIP-57457N; -. DR IntAct; P34947; 5. DR MINT; P34947; -. DR STRING; 9606.ENSP00000376609; -. DR BindingDB; P34947; -. DR ChEMBL; CHEMBL5678; -. DR GuidetoPHARMACOLOGY; 1469; -. DR iPTMnet; P34947; -. DR PhosphoSitePlus; P34947; -. DR BioMuta; GRK5; -. DR DMDM; 462203; -. DR jPOST; P34947; -. DR MassIVE; P34947; -. DR MaxQB; P34947; -. DR PaxDb; 9606-ENSP00000376609; -. DR PeptideAtlas; P34947; -. DR ProteomicsDB; 54958; -. DR ABCD; P34947; 1 sequenced antibody. DR Antibodypedia; 18824; 562 antibodies from 39 providers. DR DNASU; 2869; -. DR Ensembl; ENST00000392870.3; ENSP00000376609.2; ENSG00000198873.12. DR GeneID; 2869; -. DR KEGG; hsa:2869; -. DR MANE-Select; ENST00000392870.3; ENSP00000376609.2; NM_005308.3; NP_005299.1. DR UCSC; uc001led.4; human. DR AGR; HGNC:4544; -. DR CTD; 2869; -. DR DisGeNET; 2869; -. DR GeneCards; GRK5; -. DR HGNC; HGNC:4544; GRK5. DR HPA; ENSG00000198873; Low tissue specificity. DR MIM; 600870; gene. DR neXtProt; NX_P34947; -. DR OpenTargets; ENSG00000198873; -. DR PharmGKB; PA180; -. DR VEuPathDB; HostDB:ENSG00000198873; -. DR eggNOG; KOG0986; Eukaryota. DR GeneTree; ENSGT00940000160702; -. DR HOGENOM; CLU_000288_63_41_1; -. DR InParanoid; P34947; -. DR OMA; ISWQTEM; -. DR OrthoDB; 2906348at2759; -. DR PhylomeDB; P34947; -. DR TreeFam; TF313940; -. DR BRENDA; 2.7.11.16; 2681. DR PathwayCommons; P34947; -. DR Reactome; R-HSA-416476; G alpha (q) signalling events. DR Reactome; R-HSA-418555; G alpha (s) signalling events. DR SignaLink; P34947; -. DR SIGNOR; P34947; -. DR BioGRID-ORCS; 2869; 15 hits in 1188 CRISPR screens. DR ChiTaRS; GRK5; human. DR GeneWiki; GRK5; -. DR GenomeRNAi; 2869; -. DR Pharos; P34947; Tchem. DR PRO; PR:P34947; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; P34947; Protein. DR Bgee; ENSG00000198873; Expressed in saphenous vein and 196 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0031965; C:nuclear membrane; IDA:HPA. DR GO; GO:0016607; C:nuclear speck; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0047696; F:beta-adrenergic receptor kinase activity; IMP:CACAO. DR GO; GO:0004703; F:G protein-coupled receptor kinase activity; IEA:UniProtKB-EC. DR GO; GO:0005543; F:phospholipid binding; TAS:ProtInc. DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central. DR GO; GO:0005080; F:protein kinase C binding; TAS:ProtInc. DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0007188; P:adenylate cyclase-modulating G protein-coupled receptor signaling pathway; TAS:ProtInc. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0045444; P:fat cell differentiation; IEA:Ensembl. DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; TAS:Reactome. DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:CACAO. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0051726; P:regulation of cell cycle; IMP:CACAO. DR GO; GO:0008277; P:regulation of G protein-coupled receptor signaling pathway; TAS:ProtInc. DR GO; GO:0009966; P:regulation of signal transduction; IBA:GO_Central. DR GO; GO:0007217; P:tachykinin receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW. DR CDD; cd05632; STKc_GRK5; 1. DR Gene3D; 6.10.250.2260; -; 1. DR Gene3D; 1.10.167.10; Regulator of G-protein Signalling 4, domain 2; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR InterPro; IPR000961; AGC-kinase_C. DR InterPro; IPR000239; GPCR_kinase. DR InterPro; IPR011009; Kinase-like_dom_sf. 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 PANTHER; PTHR24355:SF27; G PROTEIN-COUPLED RECEPTOR KINASE 5; 1. DR PANTHER; PTHR24355; G PROTEIN-COUPLED RECEPTOR KINASE/RIBOSOMAL PROTEIN S6 KINASE; 1. DR Pfam; PF00069; Pkinase; 1. DR Pfam; PF00615; RGS; 1. DR PRINTS; PR00717; GPCRKINASE. DR SMART; SM00315; RGS; 1. DR SMART; SM00133; S_TK_X; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF48097; Regulator of G-protein signaling, RGS; 1. DR PROSITE; PS51285; AGC_KINASE_CTER; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS50132; RGS; 1. DR Genevisible; P34947; HS. PE 1: Evidence at protein level; KW 3D-structure; Apoptosis; ATP-binding; Cell membrane; Cytoplasm; Kinase; KW Lipid-binding; Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; KW Reference proteome; Serine/threonine-protein kinase; Transferase; KW Wnt signaling pathway. FT CHAIN 1..590 FT /note="G protein-coupled receptor kinase 5" FT /id="PRO_0000085971" FT DOMAIN 53..171 FT /note="RGS" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00171" FT DOMAIN 186..448 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT DOMAIN 449..514 FT /note="AGC-kinase C-terminal" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00618" FT REGION 1..185 FT /note="N-terminal" FT REGION 20..39 FT /note="Interaction with calmodulin" FT REGION 531..590 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 546..565 FT /note="Sufficient for membrane localization" FT MOTIF 388..395 FT /note="Nuclear localization signal" FT /evidence="ECO:0000269|PubMed:15542828" FT COMPBIAS 555..590 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 311 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 192..200 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 215 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT MOD_RES 484 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:8144599, FT ECO:0007744|PubMed:18669648" FT MOD_RES 485 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:8144599, FT ECO:0007744|PubMed:18669648" FT MOD_RES 579 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8VEB1" FT VARIANT 41 FT /note="Q -> L (exerts a protective effect in heart failure FT and ischemia; dbSNP:rs2230345)" FT /evidence="ECO:0000269|PubMed:17344846, FT ECO:0000269|PubMed:18425130" FT /id="VAR_040517" FT VARIANT 119 FT /note="A -> V (in dbSNP:rs55980792)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040518" FT VARIANT 122 FT /note="G -> S (in dbSNP:rs55902633)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040519" FT VARIANT 129 FT /note="T -> M (in dbSNP:rs34679178)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040520" FT VARIANT 141 FT /note="L -> I (in dbSNP:rs56254855)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040521" FT VARIANT 163 FT /note="D -> E (in a lung neuroendocrine carcinoma sample; FT somatic mutation)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040522" FT VARIANT 304 FT /note="R -> H (in dbSNP:rs2230349)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_040523" FT MUTAGEN 215 FT /note="K->R: Failed to phosphorylate p53/TP53." FT /evidence="ECO:0000269|PubMed:20124405" FT MUTAGEN 388 FT /note="R->A: Nuclear exclusion; when associated with A-389; FT A-391; A-393 and A-394." FT /evidence="ECO:0000269|PubMed:15542828" FT MUTAGEN 389 FT /note="K->A: Nuclear exclusion; when associated with A-388; FT A-391; A-393 and A-394." FT /evidence="ECO:0000269|PubMed:15542828" FT MUTAGEN 391 FT /note="K->A: Nuclear exclusion; when associated with A-388; FT A-389; A-393 and A-394." FT /evidence="ECO:0000269|PubMed:15542828" FT MUTAGEN 393 FT /note="K->A: Nuclear exclusion; when associated with A-388; FT A-389; A-391 and A-394." FT /evidence="ECO:0000269|PubMed:15542828" FT MUTAGEN 394 FT /note="R->A: Nuclear exclusion; when associated with A-388; FT A-389; A-391 and A-393." FT /evidence="ECO:0000269|PubMed:15542828" FT MUTAGEN 484 FT /note="S->A: 15-20 fold defects in kinase activity; when FT associated with A-485." FT /evidence="ECO:0000269|PubMed:8144599" FT MUTAGEN 485 FT /note="T->A: 15-20 fold defects in kinase activity; when FT associated with A-484." FT /evidence="ECO:0000269|PubMed:8144599" FT MUTAGEN 550 FT /note="L->A: No detectable plasma membrane localization; FT when associated with A-551; A-554; and A-555." FT /evidence="ECO:0000269|PubMed:14976207" FT MUTAGEN 551 FT /note="L->A: No detectable plasma membrane localization; FT when associated with A-550; A-554; and A-555." FT /evidence="ECO:0000269|PubMed:14976207" FT MUTAGEN 554 FT /note="L->A: No detectable plasma membrane localization; FT when associated with A-550; A-551; and A-555." FT /evidence="ECO:0000269|PubMed:14976207" FT MUTAGEN 555 FT /note="F->A: No detectable plasma membrane localization; FT when associated with A-550; A-551; and A-554." FT /evidence="ECO:0000269|PubMed:14976207" FT HELIX 3..16 FT /evidence="ECO:0007829|PDB:6PJX" FT TURN 17..20 FT /evidence="ECO:0007829|PDB:6PJX" FT HELIX 22..25 FT /evidence="ECO:0007829|PDB:6PJX" FT HELIX 30..33 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 39..42 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 43..48 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 53..57 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 61..71 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 75..91 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 95..97 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 98..109 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 123..134 FT /evidence="ECO:0007829|PDB:4TND" FT TURN 139..142 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 143..153 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 156..162 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 165..177 FT /evidence="ECO:0007829|PDB:4TND" FT STRAND 185..195 FT /evidence="ECO:0007829|PDB:4TND" FT STRAND 198..205 FT /evidence="ECO:0007829|PDB:4TND" FT TURN 206..208 FT /evidence="ECO:0007829|PDB:4TND" FT STRAND 211..218 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 219..224 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 228..240 FT /evidence="ECO:0007829|PDB:4TND" FT STRAND 249..254 FT /evidence="ECO:0007829|PDB:4TND" FT STRAND 256..263 FT /evidence="ECO:0007829|PDB:4TND" FT STRAND 268..270 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 271..277 FT /evidence="ECO:0007829|PDB:4TND" FT STRAND 278..280 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 285..304 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 314..316 FT /evidence="ECO:0007829|PDB:4TND" FT STRAND 317..319 FT /evidence="ECO:0007829|PDB:4TND" FT STRAND 325..327 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 330..332 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 354..357 FT /evidence="ECO:0007829|PDB:4TND" FT STRAND 362..364 FT /evidence="ECO:0007829|PDB:6PJX" FT HELIX 366..380 FT /evidence="ECO:0007829|PDB:4TND" FT STRAND 384..386 FT /evidence="ECO:0007829|PDB:6PJX" FT HELIX 394..403 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 414..423 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 428..430 FT /evidence="ECO:0007829|PDB:4TND" FT TURN 436..438 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 439..443 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 446..448 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 453..457 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 477..479 FT /evidence="ECO:0007829|PDB:6PJX" FT STRAND 489..491 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 494..502 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 508..517 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 520..524 FT /evidence="ECO:0007829|PDB:4TND" FT STRAND 529..531 FT /evidence="ECO:0007829|PDB:4TND" FT HELIX 535..537 FT /evidence="ECO:0007829|PDB:4TND" SQ SEQUENCE 590 AA; 67787 MW; D363567ECFF5CF21 CRC64; MELENIVANT VLLKAREGGG GKRKGKSKKW KEILKFPHIS QCEDLRRTID RDYCSLCDKQ PIGRLLFRQF CETRPGLECY IQFLDSVAEY EVTPDEKLGE KGKEIMTKYL TPKSPVFIAQ VGQDLVSQTE EKLLQKPCKE LFSACAQSVH EYLRGEPFHE YLDSMFFDRF LQWKWLERQP VTKNTFRQYR VLGKGGFGEV CACQVRATGK MYACKRLEKK RIKKRKGESM ALNEKQILEK VNSQFVVNLA YAYETKDALC LVLTIMNGGD LKFHIYNMGN PGFEEERALF YAAEILCGLE DLHRENTVYR DLKPENILLD DYGHIRISDL GLAVKIPEGD LIRGRVGTVG YMAPEVLNNQ RYGLSPDYWG LGCLIYEMIE GQSPFRGRKE KVKREEVDRR VLETEEVYSH KFSEEAKSIC KMLLTKDAKQ RLGCQEEGAA EVKRHPFFRN MNFKRLEAGM LDPPFVPDPR AVYCKDVLDI EQFSTVKGVN LDHTDDDFYS KFSTGSVSIP WQNEMIETEC FKELNVFGPN GTLPPDLNRN HPPEPPKKGL LQRLFKRQHQ NNSKSSPSSK TSFNHHINSN HVSSNSTGSS //