GRK5_MOUSE
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 03-AUG-2022, entry version 161.
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}.
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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; Q8VEB1; -.
DR PRIDE; Q8VEB1; -.
DR ProteomicsDB; 269835; -.
DR ABCD; Q8VEB1; 1 sequenced antibody.
DR Antibodypedia; 18824; 535 antibodies from 39 providers.
DR DNASU; 14773; -.
DR Ensembl; ENSMUST00000003313; ENSMUSP00000003313; ENSMUSG00000003228.
DR GeneID; 14773; -.
DR KEGG; mmu:14773; -.
DR UCSC; uc008ice.2; mouse.
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; YIVNRIF; -.
DR OrthoDB; 1104340at2759; -.
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 75 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 145 other tissues.
DR ExpressionAtlas; Q8VEB1; baseline and differential.
DR Genevisible; Q8VEB1; MM.
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:0006468; P:protein phosphorylation; IBA:GO_Central.
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 Gene3D; 1.10.167.10; -; 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 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; SSF48097; SSF48097; 1.
DR SUPFAM; SSF56112; SSF56112; 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.
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
