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Q8VEB1

- GRK5_MOUSE

UniProt

Q8VEB1 - GRK5_MOUSE

Protein

G protein-coupled receptor kinase 5

Gene

Grk5

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 107 (01 Oct 2014)
      Sequence version 2 (24 May 2004)
      Previous versions | rss
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    Functioni

    Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein-coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro).4 Publications

    Catalytic activityi

    ATP + [G-protein-coupled receptor] = ADP + [G-protein-coupled receptor] phosphate.

    Enzyme regulationi

    Inhibited by calmodulin with an IC50 of 50 nM. Calmodulin inhibits GRK5 association with receptor and phospholipid By similarity.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei215 – 2151ATPPROSITE-ProRule annotation
    Active sitei311 – 3111Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi192 – 2009ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. G-protein coupled receptor kinase activity Source: UniProtKB-EC
    3. lipid binding Source: UniProtKB-KW
    4. protein serine/threonine kinase activity Source: UniProtKB

    GO - Biological processi

    1. apoptotic process Source: UniProtKB-KW
    2. negative regulation of apoptotic process Source: UniProtKB
    3. protein autophosphorylation Source: UniProtKB
    4. tachykinin receptor signaling pathway Source: Ensembl
    5. termination of G-protein coupled receptor signaling pathway Source: InterPro
    6. Wnt signaling pathway Source: UniProtKB-KW

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Apoptosis, Wnt signaling pathway

    Keywords - Ligandi

    ATP-binding, Lipid-binding, Nucleotide-binding

    Enzyme and pathway databases

    ReactomeiREACT_207651. G alpha (q) signalling events.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    G protein-coupled receptor kinase 5 (EC:2.7.11.16)
    Alternative name(s):
    G protein-coupled receptor kinase GRK5
    Gene namesi
    Name:Grk5
    Synonyms:Gprk5
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 19

    Organism-specific databases

    MGIiMGI:109161. Grk5.

    Subcellular locationi

    Cytoplasm By similarity. Nucleus. Cell membrane; Peripheral membrane protein
    Note: Predominantly localized at the plasma membrane, targeted to the cell surface through the interaction with phospholipids. Nucleus localization is regulated in a GPCR and Ca2+/calmodulin-dependent fashion By similarity.By similarity

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB-SubCell
    2. nucleus Source: UniProtKB-SubCell
    3. plasma membrane Source: UniProtKB

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Membrane, Nucleus

    Pathology & Biotechi

    Disruption phenotypei

    No obvious phenotype due to the redundancy of GRK subtypes in the regulation of GPCR signaling. Deficient mice are viable and showed no anatomic or behavioral abnormalities, only a slight decrease in body temperature. However deficient mice shown altered central and lung M2 muscarinic receptor regulation, with normal heart M2 receptor regulation. GRK5 deficiency leads to a reduced hippocampal acetylcholine release and cholinergic hypofunction by selective impairment of desensitization of presynaptic M2/M4 autoreceptors and promotes beta-amyloid accumulation.4 Publications

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 590590G protein-coupled receptor kinase 5PRO_0000085972Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei484 – 4841Phosphoserine; by autocatalysis1 Publication
    Modified residuei485 – 4851Phosphothreonine; by autocatalysis1 Publication

    Post-translational modificationi

    Autophosphorylated. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity By similarity.By similarity

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    PaxDbiQ8VEB1.
    PRIDEiQ8VEB1.

    PTM databases

    PhosphoSiteiQ8VEB1.

    Expressioni

    Gene expression databases

    BgeeiQ8VEB1.
    CleanExiMM_GRK5.
    GenevestigatoriQ8VEB1.

    Interactioni

    Subunit structurei

    Interacts with ST13 (via the C-terminus 303-319 AA) By similarity. Interacts with TP53/p53 By similarity. Interacts with HTR4 (via C-terminus 330-346 AA); this interaction is promoted by 5-HT (serotonin) By similarity. Interacts with HDAC5.By similarity1 Publication

    Protein-protein interaction databases

    DIPiDIP-46262N.
    IntActiQ8VEB1. 1 interaction.
    MINTiMINT-4096859.

    Structurei

    3D structure databases

    ProteinModelPortaliQ8VEB1.
    SMRiQ8VEB1. Positions 2-555.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini53 – 171119RGSPROSITE-ProRule annotationAdd
    BLAST
    Domaini186 – 448263Protein kinasePROSITE-ProRule annotationAdd
    BLAST
    Domaini449 – 51466AGC-kinase C-terminalAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni1 – 185185N-terminalAdd
    BLAST
    Regioni20 – 3920Interaction with calmodulinBy similarityAdd
    BLAST
    Regioni546 – 56520Sufficient for membrane localizationBy similarityAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi388 – 3958Nuclear localization signalBy similarity

    Sequence similaritiesi

    Contains 1 AGC-kinase C-terminal domain.Curated
    Contains 1 protein kinase domain.PROSITE-ProRule annotation
    Contains 1 RGS domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00730000110512.
    HOGENOMiHOG000006742.
    HOVERGENiHBG004532.
    InParanoidiQ8VEB1.
    KOiK08291.
    OMAiEMMETEC.
    OrthoDBiEOG7V1FQK.
    PhylomeDBiQ8VEB1.
    TreeFamiTF313940.

    Family and domain databases

    InterProiIPR000961. AGC-kinase_C.
    IPR000239. GPCR_kinase.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR016137. Regulat_G_prot_signal_superfam.
    IPR000342. RGS_dom.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    [Graphical view]
    PfamiPF00069. Pkinase. 1 hit.
    PF00615. RGS. 1 hit.
    [Graphical view]
    PRINTSiPR00717. GPCRKINASE.
    SMARTiSM00315. RGS. 1 hit.
    SM00133. S_TK_X. 1 hit.
    SM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF48097. SSF48097. 1 hit.
    SSF56112. SSF56112. 1 hit.
    PROSITEiPS51285. AGC_KINASE_CTER. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS50132. RGS. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q8VEB1-1 [UniParc]FASTAAdd to Basket

    « Hide

    MELENIVANT VLLKAREGGG GKRKGKSKKW KEILKFPHIS QCEDLRRTID    50
    RDYYSLCDKQ PIGRLLFRQF CETRPGLECY IQFLDLVAEY EITPDENLGA 100
    KGKEIMTKYL TPKSPVFIAQ VGQDLVSQTE KKLLQSPCKE LFSACAQSVH 150
    DYLKGDPFHE YLDSMYFDRF LQWKWLERQP VTKNTFRQYR VLGKGGFGEV 200
    CACQVRATGK MYACKRLEKK RIKKRKGESM ALNEKQILEK VNSQFVVNLA 250
    YAYETKDALC LVLTIMNGGD LKFHIYNMGN PGFEEERALF YAAEILCGLE 300
    DLHRENTVYR DLKPENILLD DYGHIRISDL GLAVKIPEGD LIRGRVGTVG 350
    YMAPEVLNNQ RYGLSPDYWG LGCLIYEMIE GQSPFRGRKE KVKREEVDRR 400
    VLETEEVYSS KFSEEAKSIC NMLLTKDSKQ RLGCQEEGAA EVKRHPFFRN 450
    MNFKRLEAGM LDPPFVPDPR AVYCKDVLDI EQFSTVKGVN LDHTDDDFYS 500
    KFSTGSVPIP WQNEMIETEC FKELNVFGPN GTLSPDLNRS QPPEPPKKGL 550
    FHRLFRRQHQ SNSKSSPTPK TSCNHRINSN HINSNSTGSS 590
    Length:590
    Mass (Da):67,732
    Last modified:May 24, 2004 - v2
    Checksum:iF47D87397B1A2399
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti154 – 1541K → T in AAH19379. (PubMed:15489334)Curated
    Sequence conflicti316 – 3161N → D in AAC09271. (PubMed:10506199)Curated
    Sequence conflicti353 – 3531A → D in AAC09271. (PubMed:10506199)Curated
    Sequence conflicti575 – 5751H → R in AAC09271. (PubMed:10506199)Curated

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF040759
    , AF040755, AF040756, AF040757, AF040758 Genomic DNA. Translation: AAC09271.1.
    AF040746 mRNA. Translation: AAC09267.1.
    BC019379 mRNA. Translation: AAH19379.1.
    CCDSiCCDS29945.1.
    RefSeqiNP_061357.3. NM_018869.3.
    UniGeneiMm.279400.
    Mm.482751.

    Genome annotation databases

    EnsembliENSMUST00000003313; ENSMUSP00000003313; ENSMUSG00000003228.
    GeneIDi14773.
    KEGGimmu:14773.
    UCSCiuc008ice.2. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF040759
    , AF040755 , AF040756 , AF040757 , AF040758 Genomic DNA. Translation: AAC09271.1 .
    AF040746 mRNA. Translation: AAC09267.1 .
    BC019379 mRNA. Translation: AAH19379.1 .
    CCDSi CCDS29945.1.
    RefSeqi NP_061357.3. NM_018869.3.
    UniGenei Mm.279400.
    Mm.482751.

    3D structure databases

    ProteinModelPortali Q8VEB1.
    SMRi Q8VEB1. Positions 2-555.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    DIPi DIP-46262N.
    IntActi Q8VEB1. 1 interaction.
    MINTi MINT-4096859.

    PTM databases

    PhosphoSitei Q8VEB1.

    Proteomic databases

    PaxDbi Q8VEB1.
    PRIDEi Q8VEB1.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000003313 ; ENSMUSP00000003313 ; ENSMUSG00000003228 .
    GeneIDi 14773.
    KEGGi mmu:14773.
    UCSCi uc008ice.2. mouse.

    Organism-specific databases

    CTDi 2869.
    MGIi MGI:109161. Grk5.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00730000110512.
    HOGENOMi HOG000006742.
    HOVERGENi HBG004532.
    InParanoidi Q8VEB1.
    KOi K08291.
    OMAi EMMETEC.
    OrthoDBi EOG7V1FQK.
    PhylomeDBi Q8VEB1.
    TreeFami TF313940.

    Enzyme and pathway databases

    Reactomei REACT_207651. G alpha (q) signalling events.

    Miscellaneous databases

    NextBioi 286873.
    PROi Q8VEB1.
    SOURCEi Search...

    Gene expression databases

    Bgeei Q8VEB1.
    CleanExi MM_GRK5.
    Genevestigatori Q8VEB1.

    Family and domain databases

    InterProi IPR000961. AGC-kinase_C.
    IPR000239. GPCR_kinase.
    IPR011009. Kinase-like_dom.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR016137. Regulat_G_prot_signal_superfam.
    IPR000342. RGS_dom.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    [Graphical view ]
    Pfami PF00069. Pkinase. 1 hit.
    PF00615. RGS. 1 hit.
    [Graphical view ]
    PRINTSi PR00717. GPCRKINASE.
    SMARTi SM00315. RGS. 1 hit.
    SM00133. S_TK_X. 1 hit.
    SM00220. S_TKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF48097. SSF48097. 1 hit.
    SSF56112. SSF56112. 1 hit.
    PROSITEi PS51285. AGC_KINASE_CTER. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS50132. RGS. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "The GRK4 subfamily of G protein-coupled receptor kinases. Alternative splicing, gene organization, and sequence conservation."
      Premont R.T., Macrae A.D., Aparicio S.A., Kendall H.E., Welch J.E., Lefkowitz R.J.
      J. Biol. Chem. 274:29381-29389(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
      Strain: 129/SvJ.
    2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    3. "Muscarinic supersensitivity and impaired receptor desensitization in G protein-coupled receptor kinase 5-deficient mice."
      Gainetdinov R.R., Bohn L.M., Walker J.K., Laporte S.A., Macrae A.D., Caron M.G., Lefkowitz R.J., Premont R.T.
      Neuron 24:1029-1036(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE, FUNCTION.
    4. "G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation."
      Walker J.K., Gainetdinov R.R., Feldman D.S., McFawn P.K., Caron M.G., Lefkowitz R.J., Premont R.T., Fisher J.T.
      Am. J. Physiol. 286:L312-L319(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE, FUNCTION.
    5. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-484 AND THR-485, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Liver.
    6. "Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes."
      Martini J.S., Raake P., Vinge L.E., DeGeorge B.R. Jr., Chuprun J.K., Harris D.M., Gao E., Eckhart A.D., Pitcher J.A., Koch W.J.
      Proc. Natl. Acad. Sci. U.S.A. 105:12457-12462(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, FUNCTION IN PHOSPHORYLATION OF HDAC5, INTERACTION WITH HDAC5.
    7. "GRK5 deficiency leads to reduced hippocampal acetylcholine level via impaired presynaptic M2/M4 autoreceptor desensitization."
      Liu J., Rasul I., Sun Y., Wu G., Li L., Premont R.T., Suo W.Z.
      J. Biol. Chem. 284:19564-19571(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE, FUNCTION.
    8. "GRK5 deficiency accelerates beta-amyloid accumulation in Tg2576 mice via impaired cholinergic activity."
      Cheng S., Li L., He S., Liu J., Sun Y., He M., Grasing K., Premont R.T., Suo W.Z.
      J. Biol. Chem. 285:41541-41548(2010) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE.

    Entry informationi

    Entry nameiGRK5_MOUSE
    AccessioniPrimary (citable) accession number: Q8VEB1
    Secondary accession number(s): O70292, O70297
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: May 24, 2004
    Last sequence update: May 24, 2004
    Last modified: October 1, 2014
    This is version 107 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3