ID GRK5_BOVIN Reviewed; 590 AA. AC P43249; DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1995, sequence version 1. DT 04-NOV-2026, entry version 170. 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 Bos taurus (Bovine). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae; OC Bovinae; Bos. OX NCBI_TaxID=9913; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 479-491, TISSUE RP SPECIFICITY, FUNCTION, AND PHOSPHORYLATION AT SER-484 AND THR-485. RC TISSUE=Tongue epithelium; RX PubMed=8120045; DOI=10.1016/s0021-9258(17)37451-3; RA Premont R.T., Koch W.J., Inglese J., Lefkowitz R.J.; RT "Identification, purification, and characterization of GRK5, a member of RT the family of G protein-coupled receptor kinases."; RL J. Biol. Chem. 269:6832-6841(1994). 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 (Beta-2 adrenergic receptor), muscarinic CC acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), CC dopamine receptors and opioid receptors. In addition to GPCRs, also CC phosphorylates various substrates: Hsc70-interacting protein/ST13, CC TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 CC inhibits G protein independent MAPK1/MAPK3 signaling downstream of CC 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte CC enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and CC allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a CC crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. CC Phosphorylation of ST13 regulates internalization of the chemokine CC receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G CC protein-coupled receptor, LRP6 during Wnt signaling (in vitro) (By CC similarity). {ECO:0000250, ECO:0000269|PubMed:8120045}. 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 (By similarity). {ECO:0000250|UniProtKB:P34947, CC ECO:0000250|UniProtKB:Q62833, ECO:0000250|UniProtKB:Q8VEB1}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}. CC Cell membrane {ECO:0000250}; Peripheral membrane protein {ECO:0000250}. CC Note=Predominantly localized at the plasma membrane, targeted to the CC cell surface through the interaction with phospholipids. Nucleus CC localization is regulated in a GPCR and Ca(2+)/calmodulin-dependent CC fashion (By similarity). {ECO:0000250}. CC -!- TISSUE SPECIFICITY: Highest levels in lung, heart, retina, lingual CC epithelium. Very little in brain, liver, kidney. CC {ECO:0000269|PubMed:8120045}. CC -!- PTM: Autophosphorylated. Autophosphorylation may play a critical role CC in the regulation of GRK5 kinase activity. CC {ECO:0000269|PubMed:8120045}. 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; U01206; AAA17561.1; -; mRNA. DR PIR; A54372; A54372. DR RefSeq; NP_776756.1; NM_174331.2. DR PDB; 4WNK; X-ray; 2.42 A; A=1-590. DR AlphaFoldDB; P43249; -. DR MDRepo; P43249; -. DR SMR; P43249; -. DR DIP; DIP-60782N; -. DR FunCoup; P43249; 1663. DR IntAct; P43249; 2. DR STRING; 9913.ENSBTAP00000073444; -. DR BindingDB; P43249; -. DR ChEMBL; CHEMBL3879830; -. DR iPTMnet; P43249; -. DR PaxDb; 9913-ENSBTAP00000073444; -. DR GeneID; 281801; -. DR KEGG; bta:281801; -. DR CTD; 2869; -. DR VEuPathDB; HostDB:ENSBTAG00000007981; -. DR VGNC; VGNC:29656; GRK5. DR eggNOG; KOG0986; Eukaryota. DR HOGENOM; CLU_000288_63_41_1; -. DR InParanoid; P43249; -. DR OMA; ACAXQPV; -. DR OrthoDB; 354826at2759; -. DR BRENDA; 2.7.11.16; 908. DR Reactome; R-BTA-418555; G alpha (s) signalling events. DR EvolutionaryTrace; P43249; -. DR Proteomes; UP000009136; Chromosome 26. DR Bgee; ENSBTAG00000007981; Expressed in esophagus and 103 other cell types or tissues. 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:InterPro. DR GO; GO:0004703; F:G protein-coupled receptor kinase activity; IEA:UniProtKB-EC. 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:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB. DR GO; GO:0009966; P:regulation of signal transduction; IBA:GO_Central. DR GO; GO:0007165; P:signal transduction; IEA:InterPro. DR CDD; cd08752; RGS_GRK5; 1. DR CDD; cd05632; STKc_GRK5; 1. DR FunFam; 1.10.167.10:FF:000017; G protein-coupled receptor kinase; 1. DR FunFam; 1.10.510.10:FF:000074; G protein-coupled receptor kinase; 1. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 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 InterPro; IPR008271; Ser/Thr_kinase_AS. 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; PS00108; PROTEIN_KINASE_ST; 1. DR PROSITE; PS50132; RGS; 1. PE 1: Evidence at protein level; KW 3D-structure; Apoptosis; ATP-binding; Cell membrane; Cytoplasm; KW Direct protein sequencing; Kinase; Lipid-binding; Membrane; KW 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_0000085970" 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 554..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 561..590 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 311 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10027" 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:8120045" FT MOD_RES 485 FT /note="Phosphothreonine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:8120045" FT MOD_RES 579 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8VEB1" FT HELIX 30..33 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 39..42 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 43..47 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 54..59 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 61..72 FT /evidence="ECO:0007829|PDB:4WNK" FT TURN 75..77 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 78..91 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 98..109 FT /evidence="ECO:0007829|PDB:4WNK" FT STRAND 111..113 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 123..135 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 143..153 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 156..163 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 165..177 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 183..185 FT /evidence="ECO:0007829|PDB:4WNK" FT STRAND 186..194 FT /evidence="ECO:0007829|PDB:4WNK" FT STRAND 196..205 FT /evidence="ECO:0007829|PDB:4WNK" FT TURN 206..208 FT /evidence="ECO:0007829|PDB:4WNK" FT STRAND 211..218 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 219..224 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 228..240 FT /evidence="ECO:0007829|PDB:4WNK" FT STRAND 249..254 FT /evidence="ECO:0007829|PDB:4WNK" FT STRAND 256..263 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 271..275 FT /evidence="ECO:0007829|PDB:4WNK" FT STRAND 277..280 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 285..304 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 314..316 FT /evidence="ECO:0007829|PDB:4WNK" FT STRAND 317..319 FT /evidence="ECO:0007829|PDB:4WNK" FT STRAND 325..327 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 354..357 FT /evidence="ECO:0007829|PDB:4WNK" FT STRAND 362..364 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 365..380 FT /evidence="ECO:0007829|PDB:4WNK" FT STRAND 381..383 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 394..403 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 414..423 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 428..430 FT /evidence="ECO:0007829|PDB:4WNK" FT TURN 436..438 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 439..443 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 446..448 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 453..457 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 494..502 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 508..517 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 520..524 FT /evidence="ECO:0007829|PDB:4WNK" FT STRAND 529..531 FT /evidence="ECO:0007829|PDB:4WNK" FT HELIX 535..537 FT /evidence="ECO:0007829|PDB:4WNK" SQ SEQUENCE 590 AA; 67889 MW; E8F353697D8BA6E2 CRC64; MELENIVANT VLLKAREGGG GKRKGKSKKW KEILKFPHIN QCEDLRRTID RDYCSLCDKQ PVGRLLFRQF CETRPGLESY IQFLDSVAEY EVTPDEKLGE KGKEIMTKYL TPKSPVFITQ VGRDLVSQTE EKLLQKPCKE LFSACVQSVH DYLRGEPFHE YLDSMYFDRF LQWKWLERQP VTKNTFRQYR VLGKGGFGEV CACQVRATGK MYACKRLEKK RIKKRKGESM ALNEKQILEK VNSRFVVNLA YAYETKDALC LVLTIMNGGD LKFHIYNMGN PGFEEERALF YAAEILCGLE DLHHENIVYR DLKPENILLD DYGHIRISDL GLAVKIPEGD LIRGRVGTVG YMAPEVLNNQ RYGLSPDYWG LGCLIYEMIE GQSPFRGRKE KVKREEVDRR VLETEEVYSH KFSEEAKSIC KMLLTKDAKQ RLGCQEEGAA EVKRHPFFRN MNFKRLEAGM LDPPFVPDPR AVYCKDVLDI EQFSTVKGVN LDHTDDDFYS KFSTGSVPIP WQSEMIETEC FKELNVFGPH GTLSPDLNRS HPPEPPKKGL LQRLFKRQHQ NNSKSSPNSK TSFNHHINSN HVSSNSTGSS //