GRK2_CAEEL
ID GRK2_CAEEL Reviewed; 707 AA.
AC Q09639;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 23-APR-2003, sequence version 2.
DT 03-AUG-2022, entry version 163.
DE RecName: Full=G protein-coupled receptor kinase 2;
DE EC=2.7.11.16;
GN Name=grk-2; ORFNames=W02B3.2;
OS Caenorhabditis elegans.
OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC Caenorhabditis.
OX NCBI_TaxID=6239;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Bristol N2;
RX PubMed=9851916; DOI=10.1126/science.282.5396.2012;
RG The C. elegans sequencing consortium;
RT "Genome sequence of the nematode C. elegans: a platform for investigating
RT biology.";
RL Science 282:2012-2018(1998).
RN [2]
RP FUNCTION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND MUTAGENESIS OF
RP THR-354.
RX PubMed=15157420; DOI=10.1016/s0896-6273(04)00252-1;
RA Fukuto H.S., Ferkey D.M., Apicella A.J., Lans H., Sharmeen T., Chen W.,
RA Lefkowitz R.J., Jansen G., Schafer W.R., Hart A.C.;
RT "G protein-coupled receptor kinase function is essential for chemosensation
RT in C. elegans.";
RL Neuron 42:581-593(2004).
RN [3]
RP FUNCTION, AND MUTAGENESIS OF THR-354.
RX PubMed=16407969; DOI=10.1038/sj.emboj.7600940;
RA Hukema R.K., Rademakers S., Dekkers M.P., Burghoorn J., Jansen G.;
RT "Antagonistic sensory cues generate gustatory plasticity in Caenorhabditis
RT elegans.";
RL EMBO J. 25:312-322(2006).
RN [4]
RP DOMAIN, AND MUTAGENESIS OF ASP-3; LEU-4; 7-VAL-LEU-8; ASP-10; ARG-106;
RP TYR-109; ASP-110; ARG-195; LYS-220; LYS-567 AND ARG-587.
RX PubMed=22375004; DOI=10.1074/jbc.m111.336818;
RA Wood J.F., Wang J., Benovic J.L., Ferkey D.M.;
RT "Structural domains required for Caenorhabditis elegans G protein-coupled
RT receptor kinase 2 (GRK-2) function in vivo.";
RL J. Biol. Chem. 287:12634-12644(2012).
RN [5]
RP FUNCTION, INTERACTION WITH AMX-2, TISSUE SPECIFICITY, DISRUPTION PHENOTYPE,
RP AND MUTAGENESIS OF LYS-220 AND THR-354.
RX PubMed=28213524; DOI=10.1074/jbc.m116.760850;
RA Wang J., Luo J., Aryal D.K., Wetsel W.C., Nass R., Benovic J.L.;
RT "G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism
RT through the monoamine oxidase AMX-2 in Caenorhabditis elegans.";
RL J. Biol. Chem. 292:5943-5956(2017).
RN [6]
RP FUNCTION, TISSUE SPECIFICITY, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF
RP ASP-3; LEU-4; 7-VAL-LEU-8; ASP-10; ARG-106; TYR-109; ASP-110; ARG-195;
RP GLY-379; LYS-567 AND ARG-587.
RX PubMed=28968387; DOI=10.1371/journal.pgen.1007032;
RA Topalidou I., Cooper K., Pereira L., Ailion M.;
RT "Dopamine negatively modulates the NCA ion channels in C. elegans.";
RL PLoS Genet. 13:E1007032-E1007032(2017).
CC -!- FUNCTION: Specifically phosphorylates the activated forms of G protein-
CC coupled receptors (By similarity). Required in adult sensory neurons
CC for chemotaxis (PubMed:15157420). Plays a role in the ASH sensory
CC neurons in the chemotaxis response to NaCl where it is likely to
CC modulate the strength of the NaCl avoidance response which occurs at
CC high NaCl concentrations (PubMed:16407969). Required in the HSN motor
CC neurons for normal egg laying by promoting phosphorylation of amine
CC oxidase amx-2 which inhibits amx-2 activity, preventing metabolism of
CC serotonin (PubMed:28213524). Acts in head acetylcholine neurons to
CC positively regulate locomotion (PubMed:28968387). Inactivates dopamine
CC receptor dop-3 which leads to inactivation of guanine nucleotide-
CC binding protein G(o) subunit goa-1 and activation of the unc-77/nca-1
CC and nca-2 ion channel proteins (PubMed:28968387).
CC {ECO:0000250|UniProtKB:P32298, ECO:0000269|PubMed:15157420,
CC ECO:0000269|PubMed:16407969, ECO:0000269|PubMed:28213524,
CC ECO:0000269|PubMed:28968387}.
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 -!- SUBUNIT: Interacts with amx-2; the interaction promotes phosphorylation
CC of amx-2. {ECO:0000269|PubMed:28213524}.
CC -!- TISSUE SPECIFICITY: Expressed in many neurons in the adult including
CC the ASH neurons and other sensory neurons, many interneurons, and motor
CC neurons of the ventral nerve cord (PubMed:15157420). Expressed broadly
CC in head neurons and is detected in several head acetylcholine neurons
CC including the AVA, AVB, AVD and AVE premotor interneurons, the SMD and
CC RMD head motor neurons, and the AIN, AIY, SIA, SIB and SAA interneurons
CC (PubMed:28968387). Expressed in HSN motor neurons and VC4/VC5 motor
CC neurons (PubMed:28213524). Also expressed in vulval muscle cells
CC (PubMed:15157420, PubMed:28213524). {ECO:0000269|PubMed:15157420,
CC ECO:0000269|PubMed:28213524, ECO:0000269|PubMed:28968387}.
CC -!- DEVELOPMENTAL STAGE: Expression is observed in embryos as early as the
CC 20-30 cell stage and persists throughout development and into
CC adulthood. {ECO:0000269|PubMed:15157420}.
CC -!- DOMAIN: The kinase domain is required for chemotaxis activity.
CC {ECO:0000269|PubMed:22375004}.
CC -!- DISRUPTION PHENOTYPE: Defective egg-laying with mutants retaining 35
CC eggs compared to 13-14 eggs in wild-type worms (PubMed:28213524,
CC PubMed:28968387). Reduced serotonin levels, increased levels of the
CC serotonin metabolite 5-hydroxyindoleacetic acid, increased levels of
CC amine oxidase amx-2 in early adult stages and reduced levels of
CC phosphorylated amx-2 (PubMed:28213524). Defective locomotion and
CC reduced body length (PubMed:28968387). {ECO:0000269|PubMed:28213524,
CC ECO:0000269|PubMed:28968387}.
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; FO080476; CCD63981.1; -; Genomic_DNA.
DR PIR; T26096; T26096.
DR RefSeq; NP_497235.2; NM_064834.4.
DR AlphaFoldDB; Q09639; -.
DR SMR; Q09639; -.
DR BioGRID; 40494; 3.
DR IntAct; Q09639; 2.
DR MINT; Q09639; -.
DR STRING; 6239.W02B3.2; -.
DR EPD; Q09639; -.
DR PaxDb; Q09639; -.
DR PeptideAtlas; Q09639; -.
DR EnsemblMetazoa; W02B3.2.1; W02B3.2.1; WBGene00001709.
DR GeneID; 175223; -.
DR KEGG; cel:CELE_W02B3.2; -.
DR UCSC; W02B3.2; c. elegans.
DR CTD; 175223; -.
DR WormBase; W02B3.2; CE32946; WBGene00001709; grk-2.
DR eggNOG; KOG0986; Eukaryota.
DR GeneTree; ENSGT00940000169024; -.
DR HOGENOM; CLU_000288_63_41_1; -.
DR InParanoid; Q09639; -.
DR OMA; KHFSLTI; -.
DR OrthoDB; 1104340at2759; -.
DR PhylomeDB; Q09639; -.
DR Reactome; R-CEL-111933; Calmodulin induced events.
DR Reactome; R-CEL-416476; G alpha (q) signalling events.
DR PRO; PR:Q09639; -.
DR Proteomes; UP000001940; Chromosome III.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0001664; F:G protein-coupled receptor binding; IBA:GO_Central.
DR GO; GO:0004703; F:G protein-coupled receptor kinase activity; IBA:GO_Central.
DR GO; GO:0004672; F:protein kinase activity; IBA:GO_Central.
DR GO; GO:0006935; P:chemotaxis; IMP:WormBase.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IBA:GO_Central.
DR GO; GO:0006972; P:hyperosmotic response; IMP:WormBase.
DR GO; GO:0032501; P:multicellular organismal process; IGI:WormBase.
DR GO; GO:0060160; P:negative regulation of dopamine receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:0042048; P:olfactory behavior; IMP:WormBase.
DR GO; GO:2001259; P:positive regulation of cation channel activity; IMP:UniProtKB.
DR GO; GO:0050921; P:positive regulation of chemotaxis; IMP:UniProtKB.
DR GO; GO:0040010; P:positive regulation of growth rate; IGI:WormBase.
DR GO; GO:0040017; P:positive regulation of locomotion; IMP:UniProtKB.
DR GO; GO:1901046; P:positive regulation of oviposition; IMP:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IMP:UniProtKB.
DR GO; GO:0009966; P:regulation of signal transduction; IBA:GO_Central.
DR GO; GO:1902074; P:response to salt; IMP:UniProtKB.
DR GO; GO:0042429; P:serotonin catabolic process; IMP:UniProtKB.
DR Gene3D; 1.10.167.10; -; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR000961; AGC-kinase_C.
DR InterPro; IPR000239; GPCR_kinase.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
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 Pfam; PF00069; Pkinase; 1.
DR Pfam; PF00615; RGS; 1.
DR PRINTS; PR00717; GPCRKINASE.
DR SMART; SM00233; PH; 1.
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; PS50003; PH_DOMAIN; 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 ATP-binding; Chemotaxis; Kinase; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..707
FT /note="G protein-coupled receptor kinase 2"
FT /id="PRO_0000086841"
FT DOMAIN 54..175
FT /note="RGS"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00171"
FT DOMAIN 191..455
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 456..523
FT /note="AGC-kinase C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00618"
FT DOMAIN 558..658
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT REGION 1..190
FT /note="N-terminal"
FT ACT_SITE 318
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 197..205
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 220
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT SITE 3
FT /note="Required for receptor phosphorylation"
FT /evidence="ECO:0000250|UniProtKB:P25098"
FT SITE 4
FT /note="Required for receptor phosphorylation"
FT /evidence="ECO:0000250|UniProtKB:P25098"
FT SITE 10
FT /note="Required for receptor phosphorylation"
FT /evidence="ECO:0000250|UniProtKB:P25098"
FT MUTAGEN 3
FT /note="D->K: Failure to restore locomotion or avoidance to
FT the aversive compounds octanol and quinine in animals
FT lacking endogenous grk-2."
FT /evidence="ECO:0000269|PubMed:22375004,
FT ECO:0000269|PubMed:28968387"
FT MUTAGEN 4
FT /note="L->K: Failure to restore locomotion or avoidance to
FT the aversive compounds octanol and quinine in animals
FT lacking endogenous grk-2."
FT /evidence="ECO:0000269|PubMed:22375004,
FT ECO:0000269|PubMed:28968387"
FT MUTAGEN 7..8
FT /note="VL->AA: Failure to restore locomotion or avoidance
FT to the aversive compounds octanol and quinine in animals
FT lacking endogenous grk-2."
FT /evidence="ECO:0000269|PubMed:22375004,
FT ECO:0000269|PubMed:28968387"
FT MUTAGEN 10
FT /note="D->A: Failure to restore locomotion or avoidance to
FT the aversive compounds octanol and quinine in animals
FT lacking endogenous grk-2."
FT /evidence="ECO:0000269|PubMed:22375004,
FT ECO:0000269|PubMed:28968387"
FT MUTAGEN 106
FT /note="R->A: No effect on ability to restore locomotion or
FT avoidance to the aversive compounds octanol and quinine in
FT animals lacking endogenous grk-2."
FT /evidence="ECO:0000269|PubMed:22375004,
FT ECO:0000269|PubMed:28968387"
FT MUTAGEN 109
FT /note="Y->I: No effect on ability to restore locomotion or
FT avoidance to the aversive compounds octanol and quinine in
FT animals lacking endogenous grk-2."
FT /evidence="ECO:0000269|PubMed:22375004,
FT ECO:0000269|PubMed:28968387"
FT MUTAGEN 110
FT /note="D->A: No effect on ability to restore locomotion or
FT avoidance to the aversive compounds octanol and quinine in
FT animals lacking endogenous grk-2."
FT /evidence="ECO:0000269|PubMed:22375004,
FT ECO:0000269|PubMed:28968387"
FT MUTAGEN 195
FT /note="R->A: Failure to restore locomotion or avoidance to
FT the aversive compounds octanol and quinine in animals
FT lacking endogenous grk-2."
FT /evidence="ECO:0000269|PubMed:22375004,
FT ECO:0000269|PubMed:28968387"
FT MUTAGEN 220
FT /note="K->R: Failure to restore avoidance to the aversive
FT compounds octanol and quinine in animals lacking endogenous
FT grk-2. Failure to rescue defective egg laying in grk-2
FT mutants."
FT /evidence="ECO:0000269|PubMed:22375004,
FT ECO:0000269|PubMed:28213524"
FT MUTAGEN 354
FT /note="T->I: In rt97; dramatic decrease in grk-2 protein
FT levels, defective egg laying, reduced serotonin levels,
FT increased levels of the serotonin metabolite 5-
FT hydroxyindoleacetic acid, increased levels of amine oxidase
FT amx-2 in early adult stages, reduced levels of
FT phosphorylated amx-2, severe defect in octanol avoidance
FT and severely impaired chemotaxis to attractive compounds
FT including 0.1-100 mM NaCl although mutants show avoidance
FT to 25 mM NaCl after pre-exposure to 100 mM NaCl."
FT /evidence="ECO:0000269|PubMed:15157420,
FT ECO:0000269|PubMed:16407969, ECO:0000269|PubMed:28213524"
FT MUTAGEN 379
FT /note="G->E: In yak18; decreased body length, slow
FT locomotion and defective egg laying."
FT /evidence="ECO:0000269|PubMed:28968387"
FT MUTAGEN 567
FT /note="K->E: Failure to restore locomotion in animals
FT lacking endogenous grk-2. Significantly restored avoidance
FT of aversive compounds octanol and quinine in animals
FT lacking endogenous grk-2. Failure to restore avoidance to
FT octanol and quinine in animals lacking endogenous grk-2;
FT when associated with Q-587."
FT /evidence="ECO:0000269|PubMed:22375004,
FT ECO:0000269|PubMed:28968387"
FT MUTAGEN 587
FT /note="R->Q: Failure to restore locomotion in animals
FT lacking endogenous grk-2. Reduced ability to restore
FT avoidance to the aversive compounds octanol and quinine in
FT animals lacking endogenous grk-2. Failure to restore
FT avoidance to octanol and quinine in animals lacking
FT endogenous grk-2; when associated with E-567."
FT /evidence="ECO:0000269|PubMed:22375004,
FT ECO:0000269|PubMed:28968387"
SQ SEQUENCE 707 AA; 80978 MW; D37F03260F324939 CRC64;
MADLEAVLAD VSYLMAMEKS RSQPAARASK RIVLPDPSVR SIMQKFLEKS GDMKFDKIFN
QKLGFLLLKD YAENVSESPC PQIKFYEAIK EYEKMETPDE RLTKAREIYD HHIMVEMLAH
AHNYSKESLQ HVQYHLLKQN VPPDLFHRYV LEICDQLRGD IFQRFLESDK FTRFCQWKNL
ELNMQLTMND FSVHRIIGRG GFGEVYGCRK ADTGKMYAMK CLDKKRIKMK QGETLALNER
IMLSLVSTGQ DCPFIVCMTY AFQSPDKLCF ILDLMNGGDL HYHLSQHGVF TEQEMIFYAS
EVILGLEHMH NRFVVYRDLK PANILLDENG HVRVSDLGLA CDYSKKKPHA SVGTHGYMAP
EVLAKGVAYD SSADWFSLGC MLYKLLKGHS PFRQHKSKDK NEIDKMTLTQ DIELPNEGLS
KDCRDLLEGL LKRDVPDRLG CRGKGPTEVK EHPFFKDVDW QTVYLRRMTP PLIPPRGEVN
AADAFDIGNF DDDEVKGVKL QDGDSDLYKN FNIVISERWQ NEIAETIFEV VNQDADKAES
KKRSKQKIKV AVEEKDSDVI VHGYIKKLGG PFTSAWQTKY GKLYPSRLEL YPESLTAKPE
LVFMDQIEDV CAEMQTIKGE TAIIVKLRDG FKEPKICLTN SDEISLKEWH TSLRTAHKVS
QELLQRMGRK AIKIYGVNHD PMLSESERPG SVTRAFLNRA SSVDSGV
