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Q8VEB1 (GRK5_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified March 19, 2014. Version 103. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
G protein-coupled receptor kinase 5

EC=2.7.11.16
Alternative name(s):
G protein-coupled receptor kinase GRK5
Gene names
Name:Grk5
Synonyms:Gprk5
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length590 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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). Ref.3 Ref.4 Ref.6 Ref.7

Catalytic activity

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

Enzyme regulation

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

Subunit structure

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. Ref.6

Subcellular location

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. Ref.6 Ref.7

Post-translational modification

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

Disruption phenotype

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. Ref.3 Ref.4 Ref.7 Ref.8

Sequence similarities

Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily.

Contains 1 AGC-kinase C-terminal domain.

Contains 1 protein kinase domain.

Contains 1 RGS domain.

Ontologies

Keywords
   Biological processApoptosis
Wnt signaling pathway
   Cellular componentCell membrane
Cytoplasm
Membrane
Nucleus
   LigandATP-binding
Lipid-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processWnt signaling pathway

Inferred from electronic annotation. Source: UniProtKB-KW

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

negative regulation of apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

protein autophosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

tachykinin receptor signaling pathway

Inferred from electronic annotation. Source: Ensembl

termination of G-protein coupled receptor signaling pathway

Inferred from electronic annotation. Source: InterPro

   Cellular_componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

plasma membrane

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

G-protein coupled receptor kinase activity

Inferred from electronic annotation. Source: UniProtKB-EC

lipid binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein serine/threonine kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 590590G protein-coupled receptor kinase 5
PRO_0000085972

Regions

Domain53 – 171119RGS
Domain186 – 448263Protein kinase
Domain449 – 51466AGC-kinase C-terminal
Nucleotide binding192 – 2009ATP By similarity
Region1 – 185185N-terminal
Region20 – 3920Interaction with calmodulin By similarity
Region546 – 56520Sufficient for membrane localization By similarity
Motif388 – 3958Nuclear localization signal By similarity

Sites

Active site3111Proton acceptor By similarity
Binding site2151ATP By similarity

Amino acid modifications

Modified residue4841Phosphoserine; by autocatalysis Ref.5
Modified residue4851Phosphothreonine; by autocatalysis Ref.5

Experimental info

Sequence conflict1541K → T in AAH19379. Ref.2
Sequence conflict3161N → D in AAC09271. Ref.1
Sequence conflict3531A → D in AAC09271. Ref.1
Sequence conflict5751H → R in AAC09271. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Q8VEB1 [UniParc].

Last modified May 24, 2004. Version 2.
Checksum: F47D87397B1A2399

FASTA59067,732
        10         20         30         40         50         60 
MELENIVANT VLLKAREGGG GKRKGKSKKW KEILKFPHIS QCEDLRRTID RDYYSLCDKQ 

        70         80         90        100        110        120 
PIGRLLFRQF CETRPGLECY IQFLDLVAEY EITPDENLGA KGKEIMTKYL TPKSPVFIAQ 

       130        140        150        160        170        180 
VGQDLVSQTE KKLLQSPCKE LFSACAQSVH DYLKGDPFHE YLDSMYFDRF LQWKWLERQP 

       190        200        210        220        230        240 
VTKNTFRQYR VLGKGGFGEV CACQVRATGK MYACKRLEKK RIKKRKGESM ALNEKQILEK 

       250        260        270        280        290        300 
VNSQFVVNLA YAYETKDALC LVLTIMNGGD LKFHIYNMGN PGFEEERALF YAAEILCGLE 

       310        320        330        340        350        360 
DLHRENTVYR DLKPENILLD DYGHIRISDL GLAVKIPEGD LIRGRVGTVG YMAPEVLNNQ 

       370        380        390        400        410        420 
RYGLSPDYWG LGCLIYEMIE GQSPFRGRKE KVKREEVDRR VLETEEVYSS KFSEEAKSIC 

       430        440        450        460        470        480 
NMLLTKDSKQ RLGCQEEGAA EVKRHPFFRN MNFKRLEAGM LDPPFVPDPR AVYCKDVLDI 

       490        500        510        520        530        540 
EQFSTVKGVN LDHTDDDFYS KFSTGSVPIP WQNEMIETEC FKELNVFGPN GTLSPDLNRS 

       550        560        570        580        590 
QPPEPPKKGL FHRLFRRQHQ SNSKSSPTPK TSCNHRINSN HINSNSTGSS 

« Hide

References

« Hide 'large scale' references
[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]"Large-scale phosphorylation analysis of mouse liver."
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF040759 expand/collapse EMBL AC list , AF040755, AF040756, AF040757, AF040758 Genomic DNA. Translation: AAC09271.1.
AF040746 mRNA. Translation: AAC09267.1.
BC019379 mRNA. Translation: AAH19379.1.
RefSeqNP_061357.3. NM_018869.3.
UniGeneMm.279400.

3D structure databases

ProteinModelPortalQ8VEB1.
SMRQ8VEB1. Positions 2-555.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

DIPDIP-46262N.
IntActQ8VEB1. 1 interaction.
MINTMINT-4096859.

PTM databases

PhosphoSiteQ8VEB1.

Proteomic databases

PaxDbQ8VEB1.
PRIDEQ8VEB1.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000003313; ENSMUSP00000003313; ENSMUSG00000003228.
GeneID14773.
KEGGmmu:14773.
UCSCuc008ice.2. mouse.

Organism-specific databases

CTD2869.
MGIMGI:109161. Grk5.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00730000110512.
HOGENOMHOG000006742.
HOVERGENHBG004532.
InParanoidQ8VEB1.
KOK08291.
OMAEMMETEC.
OrthoDBEOG7V1FQK.
TreeFamTF313940.

Gene expression databases

ArrayExpressQ8VEB1.
BgeeQ8VEB1.
CleanExMM_GRK5.
GenevestigatorQ8VEB1.

Family and domain databases

InterProIPR000961. 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]
PfamPF00069. Pkinase. 1 hit.
PF00615. RGS. 1 hit.
[Graphical view]
PRINTSPR00717. GPCRKINASE.
SMARTSM00315. RGS. 1 hit.
SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF48097. SSF48097. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEPS51285. AGC_KINASE_CTER. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS50132. RGS. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio286873.
PROQ8VEB1.
SOURCESearch...

Entry information

Entry nameGRK5_MOUSE
AccessionPrimary (citable) accession number: Q8VEB1
Secondary accession number(s): O70292, O70297
Entry history
Integrated into UniProtKB/Swiss-Prot: May 24, 2004
Last sequence update: May 24, 2004
Last modified: March 19, 2014
This is version 103 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot