GRK5_RAT
ID GRK5_RAT Reviewed; 590 AA.
AC Q62833;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 144.
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 Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8626574; DOI=10.1074/jbc.271.17.10143;
RA Nagayama Y., Tanaka K., Hara T., Namba H., Yamashita S., Taniyama K.,
RA Niwa M.;
RT "Involvement of G protein-coupled receptor kinase 5 in homologous
RT desensitization of the thyrotropin receptor.";
RL J. Biol. Chem. 271:10143-10148(1996).
RN [2]
RP FUNCTION.
RX PubMed=8631993; DOI=10.1074/jbc.271.7.3771;
RA Tiberi M., Nash S.R., Bertrand L., Lefkowitz R.J., Caron M.G.;
RT "Differential regulation of dopamine D1A receptor responsiveness by various
RT G protein-coupled receptor kinases.";
RL J. Biol. Chem. 271:3771-3778(1996).
RN [3]
RP INTERACTION WITH GIT1.
RX PubMed=9826657; DOI=10.1073/pnas.95.24.14082;
RA Premont R.T., Claing A., Vitale N., Freeman J.L.R., Pitcher J.A.,
RA Patton W.A., Moss J., Vaughan M., Lefkowitz R.J.;
RT "Beta2-adrenergic receptor regulation by GIT1, a G protein-coupled receptor
RT kinase-associated ADP ribosylation factor GTPase-activating protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:14082-14087(1998).
RN [4]
RP INDUCTION.
RX PubMed=11709416; DOI=10.1152/ajpheart.2001.281.6.h2490;
RA Vinge L.E., Oie E., Andersson Y., Grogaard H.K., Andersen G.,
RA Attramadal H.;
RT "Myocardial distribution and regulation of GRK and beta-arrestin isoforms
RT in congestive heart failure in rats.";
RL Am. J. Physiol. 281:H2490-H2499(2001).
RN [5]
RP TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=11687284; DOI=10.1016/s0006-8993(01)03046-3;
RA Erdtmann-Vourliotis M., Mayer P., Ammon S., Riechert U., Hollt V.;
RT "Distribution of G-protein-coupled receptor kinase (GRK) isoforms 2, 3, 5
RT and 6 mRNA in the rat brain.";
RL Brain Res. Mol. Brain Res. 95:129-137(2001).
RN [6]
RP SUBCELLULAR LOCATION.
RX PubMed=12052842; DOI=10.1161/01.hyp.0000019130.09167.3b;
RA Yi X.P., Gerdes A.M., Li F.;
RT "Myocyte redistribution of GRK2 and GRK5 in hypertensive, heart-failure-
RT prone rats.";
RL Hypertension 39:1058-1063(2002).
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 (By similarity).
CC Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled
CC receptor, LRP6 during Wnt signaling (in vitro) (By similarity).
CC {ECO:0000250, ECO:0000269|PubMed:8631993}.
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) (By similarity). Interacts with HDAC5 (By similarity).
CC Interacts with GIT1 (PubMed:9826657). {ECO:0000250|UniProtKB:P34947,
CC ECO:0000250|UniProtKB:Q8VEB1, ECO:0000269|PubMed:9826657}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12052842}. Nucleus
CC {ECO:0000269|PubMed:12052842}. Cell membrane {ECO:0000250}; Peripheral
CC membrane protein {ECO:0000250}. Note=Predominantly localized at the
CC plasma membrane, targeted to the cell surface through the interaction
CC with phospholipids. Nucleus localization is regulated in a GPCR and
CC Ca(2+)/calmodulin-dependent fashion (By similarity). {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Not expressed ubiquitously in brain but is mainly
CC localize in limbic brain regions with a very prominent expression in
CC the lateral septal area. {ECO:0000269|PubMed:11687284}.
CC -!- INDUCTION: By cocaine in the lateral septum. Up-regulated in the
CC failing heart. {ECO:0000269|PubMed:11687284,
CC ECO:0000269|PubMed:11709416}.
CC -!- PTM: Autophosphorylated. Autophosphorylation may play a critical role
CC in the regulation of GRK5 kinase activity.
CC {ECO:0000250|UniProtKB:P34947}.
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; U34841; AAC52536.1; -; mRNA.
DR RefSeq; NP_110456.1; NM_030829.1.
DR AlphaFoldDB; Q62833; -.
DR SMR; Q62833; -.
DR STRING; 10116.ENSRNOP00000015687; -.
DR iPTMnet; Q62833; -.
DR PhosphoSitePlus; Q62833; -.
DR PaxDb; Q62833; -.
DR PRIDE; Q62833; -.
DR ABCD; Q62833; 1 sequenced antibody.
DR GeneID; 59075; -.
DR KEGG; rno:59075; -.
DR CTD; 2869; -.
DR RGD; 61985; Grk5.
DR eggNOG; KOG0986; Eukaryota.
DR InParanoid; Q62833; -.
DR PhylomeDB; Q62833; -.
DR BRENDA; 2.7.11.16; 5301.
DR Reactome; R-RNO-418555; G alpha (s) signalling events.
DR PRO; PR:Q62833; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
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:RGD.
DR GO; GO:0004703; F:G protein-coupled receptor kinase activity; IC:RGD.
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; IMP:RGD.
DR GO; GO:0045444; P:fat cell differentiation; ISO:RGD.
DR GO; GO:0106072; P:negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway; IMP:RGD.
DR GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0048709; P:oligodendrocyte differentiation; IEP:RGD.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:RGD.
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:RGD.
DR GO; GO:0008277; P:regulation of G protein-coupled receptor signaling pathway; IMP:RGD.
DR GO; GO:0009966; P:regulation of signal transduction; IBA:GO_Central.
DR GO; GO:0042220; P:response to cocaine; IEP:RGD.
DR GO; GO:0043278; P:response to morphine; IEP:RGD.
DR GO; GO:0007217; P:tachykinin receptor signaling pathway; ISO:RGD.
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_0000085973"
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 558..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:0000250|UniProtKB:Q8VEB1"
FT MOD_RES 484
FT /note="Phosphoserine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P43249"
FT MOD_RES 485
FT /note="Phosphothreonine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P43249"
FT MOD_RES 579
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8VEB1"
SQ SEQUENCE 590 AA; 67783 MW; DCAE0C00B1247AFA CRC64;
MELENIVANT VLLKAREGGG GKRKGKSKKW KEILKFPHIN QCEDLRRTID RDYYSLCDKQ
PIGRLLFRQF CETRPGLECY IQFLDLVAEY EITPDENLGA KGKEIMTKYL SPKSPVFIAQ
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 VLETEEVYSP KFSEEAKSIC
NMLLTKDSKQ RLGCQEEGAA EVKRHPFFRN MNFKRLEAGM LDPPFVPDPR AVYCKDVLDI
EQFSTVKGVN LDHTDDDFYS KFSTGSVPIP WQNEMIETEC FKELNVFGPN GTLSPDLNRS
QPPEPPKKGL FHRLFRRQHQ NNSKSSPTPK TSCNHRINSN HINSNSTGSS
