Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.
Protein

G protein-coupled receptor kinase 5

Gene

Grk5

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: 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)DescriptionActionsGraphical viewLength
Binding sitei215ATPPROSITE-ProRule annotation1
Active sitei311Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi192 – 200ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

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

BRENDAi2.7.11.16. 3474.
ReactomeiR-MMU-418555. G alpha (s) 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
Proteomesi
  • UP000000589 Componenti: 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

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)DescriptionActionsGraphical viewLength
ChainiPRO_00000859721 – 590G protein-coupled receptor kinase 5Add BLAST590

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei136PhosphoserineCombined sources1
Modified residuei484Phosphoserine; by autocatalysisCombined sources1
Modified residuei485Phosphothreonine; by autocatalysisCombined sources1
Modified residuei579PhosphoserineCombined sources1

Post-translational modificationi

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

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiQ8VEB1.
PaxDbiQ8VEB1.
PRIDEiQ8VEB1.

PTM databases

iPTMnetiQ8VEB1.
PhosphoSitePlusiQ8VEB1.

Expressioni

Gene expression databases

BgeeiENSMUSG00000003228.
CleanExiMM_GRK5.
ExpressionAtlasiQ8VEB1. baseline and differential.
GenevisibleiQ8VEB1. MM.

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 interactor.
MINTiMINT-4096859.
STRINGi10090.ENSMUSP00000003313.

Structurei

3D structure databases

ProteinModelPortaliQ8VEB1.
SMRiQ8VEB1.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini53 – 171RGSPROSITE-ProRule annotationAdd BLAST119
Domaini186 – 448Protein kinasePROSITE-ProRule annotationAdd BLAST263
Domaini449 – 514AGC-kinase C-terminalAdd BLAST66

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 185N-terminalAdd BLAST185
Regioni20 – 39Interaction with calmodulinBy similarityAdd BLAST20
Regioni546 – 565Sufficient for membrane localizationBy similarityAdd BLAST20

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi388 – 395Nuclear localization signalBy similarity8

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

eggNOGiKOG0986. Eukaryota.
ENOG410YRQZ. LUCA.
GeneTreeiENSGT00860000133699.
HOGENOMiHOG000006742.
HOVERGENiHBG004532.
InParanoidiQ8VEB1.
KOiK08291.
OMAiEFENSMY.
OrthoDBiEOG091G062G.
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. RGS.
[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)DescriptionActionsGraphical viewLength
Sequence conflicti154K → T in AAH19379 (PubMed:15489334).Curated1
Sequence conflicti316N → D in AAC09271 (PubMed:10506199).Curated1
Sequence conflicti353A → D in AAC09271 (PubMed:10506199).Curated1
Sequence conflicti575H → R in AAC09271 (PubMed:10506199).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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:
EMBLi
GenBanki
DDBJi
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.

3D structure databases

ProteinModelPortaliQ8VEB1.
SMRiQ8VEB1.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-46262N.
IntActiQ8VEB1. 1 interactor.
MINTiMINT-4096859.
STRINGi10090.ENSMUSP00000003313.

PTM databases

iPTMnetiQ8VEB1.
PhosphoSitePlusiQ8VEB1.

Proteomic databases

MaxQBiQ8VEB1.
PaxDbiQ8VEB1.
PRIDEiQ8VEB1.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi2869.
MGIiMGI:109161. Grk5.

Phylogenomic databases

eggNOGiKOG0986. Eukaryota.
ENOG410YRQZ. LUCA.
GeneTreeiENSGT00860000133699.
HOGENOMiHOG000006742.
HOVERGENiHBG004532.
InParanoidiQ8VEB1.
KOiK08291.
OMAiEFENSMY.
OrthoDBiEOG091G062G.
PhylomeDBiQ8VEB1.
TreeFamiTF313940.

Enzyme and pathway databases

BRENDAi2.7.11.16. 3474.
ReactomeiR-MMU-418555. G alpha (s) signalling events.

Miscellaneous databases

ChiTaRSiGrk5. mouse.
PROiQ8VEB1.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000003228.
CleanExiMM_GRK5.
ExpressionAtlasiQ8VEB1. baseline and differential.
GenevisibleiQ8VEB1. MM.

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. RGS.
[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]
ProtoNetiSearch...

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: November 30, 2016
This is version 130 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.