ID GRK5_MOUSE Reviewed; 590 AA. AC Q8VEB1; O70292; O70297; DT 24-MAY-2004, integrated into UniProtKB/Swiss-Prot. DT 24-MAY-2004, sequence version 2. DT 27-MAR-2024, entry version 169. 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 Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. RC STRAIN=129/SvJ; RX PubMed=10506199; DOI=10.1074/jbc.274.41.29381; RA Premont R.T., Macrae A.D., Aparicio S.A., Kendall H.E., Welch J.E., RA Lefkowitz R.J.; RT "The GRK4 subfamily of G protein-coupled receptor kinases. Alternative RT splicing, gene organization, and sequence conservation."; RL J. Biol. Chem. 274:29381-29389(1999). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [3] RP DISRUPTION PHENOTYPE, AND FUNCTION. RX PubMed=10624964; DOI=10.1016/s0896-6273(00)81048-x; RA Gainetdinov R.R., Bohn L.M., Walker J.K., Laporte S.A., Macrae A.D., RA Caron M.G., Lefkowitz R.J., Premont R.T.; RT "Muscarinic supersensitivity and impaired receptor desensitization in G RT protein-coupled receptor kinase 5-deficient mice."; RL Neuron 24:1029-1036(1999). RN [4] RP DISRUPTION PHENOTYPE, AND FUNCTION. RX PubMed=14565944; DOI=10.1152/ajplung.00255.2003; RA Walker J.K., Gainetdinov R.R., Feldman D.S., McFawn P.K., Caron M.G., RA Lefkowitz R.J., Premont R.T., Fisher J.T.; RT "G protein-coupled receptor kinase 5 regulates airway responses induced by RT muscarinic receptor activation."; RL Am. J. Physiol. 286:L312-L319(2004). RN [5] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-484 AND THR-485, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=17242355; DOI=10.1073/pnas.0609836104; RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.; RT "Large-scale phosphorylation analysis of mouse liver."; RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007). RN [6] RP SUBCELLULAR LOCATION, FUNCTION IN PHOSPHORYLATION OF HDAC5, AND INTERACTION RP WITH HDAC5. RX PubMed=18711143; DOI=10.1073/pnas.0803153105; RA Martini J.S., Raake P., Vinge L.E., DeGeorge B.R. Jr., Chuprun J.K., RA Harris D.M., Gao E., Eckhart A.D., Pitcher J.A., Koch W.J.; RT "Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase RT kinase in the nucleus of cardiomyocytes."; RL Proc. Natl. Acad. Sci. U.S.A. 105:12457-12462(2008). RN [7] RP SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, AND FUNCTION. RX PubMed=19478075; DOI=10.1074/jbc.m109.005959; RA Liu J., Rasul I., Sun Y., Wu G., Li L., Premont R.T., Suo W.Z.; RT "GRK5 deficiency leads to reduced hippocampal acetylcholine level via RT impaired presynaptic M2/M4 autoreceptor desensitization."; RL J. Biol. Chem. 284:19564-19571(2009). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-136; SER-484; THR-485 AND RP SER-579, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, Kidney, and Lung; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [9] RP DISRUPTION PHENOTYPE. RX PubMed=21041302; DOI=10.1074/jbc.m110.170894; RA Cheng S., Li L., He S., Liu J., Sun Y., He M., Grasing K., Premont R.T., RA Suo W.Z.; RT "GRK5 deficiency accelerates beta-amyloid accumulation in Tg2576 mice via RT impaired cholinergic activity."; RL J. Biol. Chem. 285:41541-41548(2010). 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:10624964, CC ECO:0000269|PubMed:14565944, ECO:0000269|PubMed:18711143, CC ECO:0000269|PubMed:19478075}. 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 (By CC similarity). {ECO:0000250}. CC -!- SUBUNIT: Interacts with ST13 (via the C-terminus 303-319 AA) (By CC similarity). Interacts with TP53/p53 (By similarity). Interacts with CC HTR4 (via C-terminus 330-346 AA); this interaction is promoted by 5-HT CC (serotonin) (PubMed:18711143). Interacts with HDAC5 (By similarity). CC Interacts with GIT1 (By similarity). {ECO:0000250|UniProtKB:P34947, CC ECO:0000250|UniProtKB:Q62833, ECO:0000269|PubMed:18711143}. CC -!- INTERACTION: CC Q8VEB1; Q9UQL6: HDAC5; Xeno; NbExp=2; IntAct=EBI-8367081, EBI-715576; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus. Cell membrane; CC Peripheral membrane protein. Note=Predominantly localized at the plasma CC membrane, 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 (By similarity). {ECO:0000250}. CC -!- PTM: Autophosphorylated. Autophosphorylation may play a critical role CC in the regulation of GRK5 kinase activity. CC {ECO:0000250|UniProtKB:P34947}. CC -!- DISRUPTION PHENOTYPE: No obvious phenotype due to the redundancy of GRK CC subtypes in the regulation of GPCR signaling. Deficient mice are viable CC and showed no anatomic or behavioral abnormalities, only a slight CC decrease in body temperature. However deficient mice shown altered CC central and lung M2 muscarinic receptor regulation, with normal heart CC M2 receptor regulation. GRK5 deficiency leads to a reduced hippocampal CC acetylcholine release and cholinergic hypofunction by selective CC impairment of desensitization of presynaptic M2/M4 autoreceptors and CC promotes amyloid-beta accumulation. {ECO:0000269|PubMed:10624964, CC ECO:0000269|PubMed:14565944, ECO:0000269|PubMed:19478075, CC ECO:0000269|PubMed:21041302}. 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; AF040759; AAC09271.1; -; Genomic_DNA. DR EMBL; AF040755; AAC09271.1; JOINED; Genomic_DNA. DR EMBL; AF040756; AAC09271.1; JOINED; Genomic_DNA. DR EMBL; AF040757; AAC09271.1; JOINED; Genomic_DNA. DR EMBL; AF040758; AAC09271.1; JOINED; Genomic_DNA. DR EMBL; AF040746; AAC09267.1; -; mRNA. DR EMBL; BC019379; AAH19379.1; -; mRNA. DR CCDS; CCDS29945.1; -. DR RefSeq; NP_061357.3; NM_018869.3. DR AlphaFoldDB; Q8VEB1; -. DR SMR; Q8VEB1; -. DR BioGRID; 200036; 2. DR DIP; DIP-46262N; -. DR IntAct; Q8VEB1; 2. DR MINT; Q8VEB1; -. DR STRING; 10090.ENSMUSP00000003313; -. DR ChEMBL; CHEMBL3721302; -. DR iPTMnet; Q8VEB1; -. DR PhosphoSitePlus; Q8VEB1; -. DR jPOST; Q8VEB1; -. DR MaxQB; Q8VEB1; -. DR PaxDb; 10090-ENSMUSP00000003313; -. DR ProteomicsDB; 269835; -. DR ABCD; Q8VEB1; 1 sequenced antibody. DR Antibodypedia; 18824; 562 antibodies from 39 providers. DR DNASU; 14773; -. DR Ensembl; ENSMUST00000003313.10; ENSMUSP00000003313.9; ENSMUSG00000003228.10. DR GeneID; 14773; -. DR KEGG; mmu:14773; -. DR UCSC; uc008ice.2; mouse. DR AGR; MGI:109161; -. DR CTD; 2869; -. DR MGI; MGI:109161; Grk5. DR VEuPathDB; HostDB:ENSMUSG00000003228; -. DR eggNOG; KOG0986; Eukaryota. DR GeneTree; ENSGT00940000160702; -. DR HOGENOM; CLU_000288_63_41_1; -. DR InParanoid; Q8VEB1; -. DR OMA; ISWQTEM; -. DR OrthoDB; 2906348at2759; -. DR PhylomeDB; Q8VEB1; -. DR TreeFam; TF313940; -. DR BRENDA; 2.7.11.16; 3474. DR Reactome; R-MMU-418555; G alpha (s) signalling events. DR BioGRID-ORCS; 14773; 3 hits in 80 CRISPR screens. DR ChiTaRS; Grk5; mouse. DR PRO; PR:Q8VEB1; -. DR Proteomes; UP000000589; Chromosome 19. DR RNAct; Q8VEB1; Protein. DR Bgee; ENSMUSG00000003228; Expressed in blood and 147 other cell types or tissues. DR ExpressionAtlas; Q8VEB1; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005829; C:cytosol; ISO:MGI. DR GO; GO:0031965; C:nuclear membrane; ISO:MGI. DR GO; GO:0016607; C:nuclear speck; ISO:MGI. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0047696; F:beta-adrenergic receptor kinase activity; ISO:MGI. DR GO; GO:0004703; F:G protein-coupled receptor kinase activity; IEA:UniProtKB-EC. DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW. DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central. DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0002029; P:desensitization of G protein-coupled receptor signaling pathway; ISO:MGI. DR GO; GO:0045444; P:fat cell differentiation; IMP:CACAO. DR GO; GO:0106072; P:negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway; ISO:MGI. DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB. DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:MGI. DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB. DR GO; GO:0051726; P:regulation of cell cycle; ISO:MGI. DR GO; GO:0008277; P:regulation of G protein-coupled receptor signaling pathway; ISO:MGI. DR GO; GO:0009966; P:regulation of signal transduction; IBA:GO_Central. DR GO; GO:0007217; P:tachykinin receptor signaling pathway; ISO:MGI. DR GO; GO:0016055; P:Wnt signaling pathway; IEA:UniProtKB-KW. DR CDD; cd05632; STKc_GRK5; 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; Q8VEB1; MM. PE 1: Evidence at protein level; KW Apoptosis; ATP-binding; Cell membrane; Cytoplasm; Kinase; Lipid-binding; KW Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome; KW Serine/threonine-protein kinase; Transferase; Wnt signaling pathway. FT CHAIN 1..590 FT /note="G protein-coupled receptor kinase 5" FT /id="PRO_0000085972" 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 /evidence="ECO:0000250" FT REGION 546..565 FT /note="Sufficient for membrane localization" FT /evidence="ECO:0000250" FT REGION 557..590 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 388..395 FT /note="Nuclear localization signal" FT /evidence="ECO:0000250" FT COMPBIAS 560..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 136 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 484 FT /note="Phosphoserine; by autocatalysis" FT /evidence="ECO:0007744|PubMed:17242355, FT ECO:0007744|PubMed:21183079" FT MOD_RES 485 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0007744|PubMed:17242355, FT ECO:0007744|PubMed:21183079" FT MOD_RES 579 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT CONFLICT 154 FT /note="K -> T (in Ref. 2; AAH19379)" FT /evidence="ECO:0000305" FT CONFLICT 316 FT /note="N -> D (in Ref. 1; AAC09271)" FT /evidence="ECO:0000305" FT CONFLICT 353 FT /note="A -> D (in Ref. 1; AAC09271)" FT /evidence="ECO:0000305" FT CONFLICT 575 FT /note="H -> R (in Ref. 1; AAC09271)" FT /evidence="ECO:0000305" SQ SEQUENCE 590 AA; 67732 MW; F47D87397B1A2399 CRC64; MELENIVANT VLLKAREGGG GKRKGKSKKW KEILKFPHIS QCEDLRRTID RDYYSLCDKQ PIGRLLFRQF CETRPGLECY IQFLDLVAEY EITPDENLGA KGKEIMTKYL TPKSPVFIAQ VGQDLVSQTE KKLLQSPCKE LFSACAQSVH DYLKGDPFHE YLDSMYFDRF LQWKWLERQP VTKNTFRQYR VLGKGGFGEV CACQVRATGK MYACKRLEKK RIKKRKGESM ALNEKQILEK VNSQFVVNLA YAYETKDALC LVLTIMNGGD LKFHIYNMGN PGFEEERALF YAAEILCGLE DLHRENTVYR DLKPENILLD DYGHIRISDL GLAVKIPEGD LIRGRVGTVG YMAPEVLNNQ RYGLSPDYWG LGCLIYEMIE GQSPFRGRKE KVKREEVDRR VLETEEVYSS KFSEEAKSIC NMLLTKDSKQ RLGCQEEGAA EVKRHPFFRN MNFKRLEAGM LDPPFVPDPR AVYCKDVLDI EQFSTVKGVN LDHTDDDFYS KFSTGSVPIP WQNEMIETEC FKELNVFGPN GTLSPDLNRS QPPEPPKKGL FHRLFRRQHQ SNSKSSPTPK TSCNHRINSN HINSNSTGSS //