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Q8VEB1

- GRK5_MOUSE

UniProt

Q8VEB1 - GRK5_MOUSE

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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

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
Complete GO annotation...

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-KW
  2. nucleus Source: UniProtKB-KW
  3. plasma membrane Source: UniProtKB
Complete GO annotation...

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

MaxQBiQ8VEB1.
PaxDbiQ8VEB1.
PRIDEiQ8VEB1.

PTM databases

PhosphoSiteiQ8VEB1.

Expressioni

Gene expression databases

BgeeiQ8VEB1.
CleanExiMM_GRK5.
ExpressionAtlasiQ8VEB1. baseline and differential.
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.
GeneTreeiENSGT00760000118793.
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.
[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

        10         20         30         40         50
MELENIVANT VLLKAREGGG GKRKGKSKKW KEILKFPHIS QCEDLRRTID
60 70 80 90 100
RDYYSLCDKQ PIGRLLFRQF CETRPGLECY IQFLDLVAEY EITPDENLGA
110 120 130 140 150
KGKEIMTKYL TPKSPVFIAQ VGQDLVSQTE KKLLQSPCKE LFSACAQSVH
160 170 180 190 200
DYLKGDPFHE YLDSMYFDRF LQWKWLERQP VTKNTFRQYR VLGKGGFGEV
210 220 230 240 250
CACQVRATGK MYACKRLEKK RIKKRKGESM ALNEKQILEK VNSQFVVNLA
260 270 280 290 300
YAYETKDALC LVLTIMNGGD LKFHIYNMGN PGFEEERALF YAAEILCGLE
310 320 330 340 350
DLHRENTVYR DLKPENILLD DYGHIRISDL GLAVKIPEGD LIRGRVGTVG
360 370 380 390 400
YMAPEVLNNQ RYGLSPDYWG LGCLIYEMIE GQSPFRGRKE KVKREEVDRR
410 420 430 440 450
VLETEEVYSS KFSEEAKSIC NMLLTKDSKQ RLGCQEEGAA EVKRHPFFRN
460 470 480 490 500
MNFKRLEAGM LDPPFVPDPR AVYCKDVLDI EQFSTVKGVN LDHTDDDFYS
510 520 530 540 550
KFSTGSVPIP WQNEMIETEC FKELNVFGPN GTLSPDLNRS QPPEPPKKGL
560 570 580 590
FHRLFRRQHQ SNSKSSPTPK TSCNHRINSN HINSNSTGSS
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

MaxQBi Q8VEB1.
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 ENSGT00760000118793.
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.
ExpressionAtlasi Q8VEB1. baseline and differential.
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.
[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

« Hide 'large scale' publications
  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 29, 2014
This is version 108 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