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Protein

G protein-coupled receptor kinase 5

Gene

GRK5

Organism
Homo sapiens (Human)
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).5 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.1 Publication

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

  • ATP binding Source: UniProtKB-KW
  • beta-adrenergic receptor kinase activity Source: CACAO
  • G-protein coupled receptor kinase activity Source: UniProtKB-EC
  • phospholipid binding Source: ProtInc
  • protein kinase C binding Source: ProtInc
  • protein serine/threonine kinase activity Source: UniProtKB

GO - Biological processi

  • adenylate cyclase-modulating G-protein coupled receptor signaling pathway Source: ProtInc
  • apoptotic process Source: UniProtKB-KW
  • fat cell differentiation Source: Ensembl
  • negative regulation of apoptotic process Source: UniProtKB
  • positive regulation of cell proliferation Source: CACAO
  • protein autophosphorylation Source: UniProtKB
  • regulation of cell cycle Source: CACAO
  • regulation of G-protein coupled receptor protein signaling pathway Source: ProtInc
  • tachykinin receptor signaling pathway Source: BHF-UCL
  • 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

BioCyciZFISH:HS01823-MONOMER.
BRENDAi2.7.11.16. 2681.
ReactomeiR-HSA-416476. G alpha (q) signalling events.
R-HSA-418555. G alpha (s) signalling events.
SignaLinkiP34947.
SIGNORiP34947.

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
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 10

Organism-specific databases

HGNCiHGNC:4544. GRK5.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: HPA
  • focal adhesion Source: HPA
  • nuclear membrane Source: HPA
  • nucleus Source: HPA
  • plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi215K → R: Failed to phosphorylate p53/TP53. 1 Publication1
Mutagenesisi388R → A: Nuclear exclusion; when associated with A-389; A-391; A-393 and A-394. 1 Publication1
Mutagenesisi389K → A: Nuclear exclusion; when associated with A-388; A-391; A-393 and A-394. 1 Publication1
Mutagenesisi391K → A: Nuclear exclusion; when associated with A-388; A-389; A-393 and A-394. 1 Publication1
Mutagenesisi393K → A: Nuclear exclusion; when associated with A-388; A-389; A-391 and A-394. 1 Publication1
Mutagenesisi394R → A: Nuclear exclusion; when associated with A-388; A-389; A-391 and A-393. 1 Publication1
Mutagenesisi484S → A: 15-20 fold defects in kinase activity; when associated with A-485. 1 Publication1
Mutagenesisi485T → A: 15-20 fold defects in kinase activity; when associated with A-484. 1 Publication1
Mutagenesisi550L → A: No detectable plasma membrane localization; when associated with A-551; A-554; and A-555. 1 Publication1
Mutagenesisi551L → A: No detectable plasma membrane localization; when associated with A-550; A-554; and A-555. 1 Publication1
Mutagenesisi554L → A: No detectable plasma membrane localization; when associated with A-550; A-551; and A-555. 1 Publication1
Mutagenesisi555F → A: No detectable plasma membrane localization; when associated with A-550; A-551; and A-554. 1 Publication1

Organism-specific databases

DisGeNETi2869.
OpenTargetsiENSG00000198873.
PharmGKBiPA180.

Chemistry databases

ChEMBLiCHEMBL5678.
GuidetoPHARMACOLOGYi1469.

Polymorphism and mutation databases

BioMutaiGRK5.
DMDMi462203.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000859711 – 590G protein-coupled receptor kinase 5Add BLAST590

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei484Phosphoserine; by autocatalysisCombined sources1 Publication1
Modified residuei485Phosphothreonine; by autocatalysisCombined sources1 Publication1
Modified residuei579PhosphoserineBy similarity1

Post-translational modificationi

Autophosphorylated. Autophosphorylation may play a critical role in the regulation of GRK5 kinase activity.1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiP34947.
PaxDbiP34947.
PeptideAtlasiP34947.
PRIDEiP34947.

PTM databases

iPTMnetiP34947.
PhosphoSitePlusiP34947.

Expressioni

Tissue specificityi

Highest levels in heart, placenta, lung > skeletal muscle > brain, liver, pancreas > kidney.1 Publication

Inductioni

Overexpressed during heart failure.1 Publication

Gene expression databases

BgeeiENSG00000198873.
CleanExiHS_GRK5.
GenevisibleiP34947. HS.

Organism-specific databases

HPAiCAB025579.
HPA046838.

Interactioni

Subunit structurei

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

Binary interactionsi

WithEntry#Exp.IntActNotes
Htr4P972888EBI-7149314,EBI-7149283From a different organism.

GO - Molecular functioni

  • protein kinase C binding Source: ProtInc

Protein-protein interaction databases

BioGridi109127. 172 interactors.
DIPiDIP-57457N.
IntActiP34947. 2 interactors.
MINTiMINT-3013589.
STRINGi9606.ENSP00000376609.

Chemistry databases

BindingDBiP34947.

Structurei

Secondary structure

1590
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi30 – 33Combined sources4
Helixi39 – 42Combined sources4
Helixi43 – 48Combined sources6
Helixi53 – 57Combined sources5
Helixi61 – 71Combined sources11
Helixi75 – 91Combined sources17
Helixi95 – 97Combined sources3
Helixi98 – 109Combined sources12
Helixi123 – 134Combined sources12
Turni139 – 142Combined sources4
Helixi143 – 153Combined sources11
Helixi156 – 162Combined sources7
Helixi165 – 177Combined sources13
Beta strandi185 – 195Combined sources11
Beta strandi198 – 205Combined sources8
Turni206 – 208Combined sources3
Beta strandi211 – 218Combined sources8
Helixi219 – 224Combined sources6
Helixi228 – 240Combined sources13
Beta strandi249 – 254Combined sources6
Beta strandi256 – 263Combined sources8
Beta strandi268 – 270Combined sources3
Helixi271 – 277Combined sources7
Beta strandi278 – 280Combined sources3
Helixi285 – 304Combined sources20
Helixi314 – 316Combined sources3
Beta strandi317 – 319Combined sources3
Beta strandi325 – 327Combined sources3
Helixi330 – 332Combined sources3
Helixi354 – 357Combined sources4
Helixi366 – 380Combined sources15
Helixi394 – 403Combined sources10
Helixi414 – 423Combined sources10
Helixi428 – 430Combined sources3
Turni436 – 438Combined sources3
Helixi439 – 443Combined sources5
Helixi446 – 448Combined sources3
Helixi453 – 457Combined sources5
Beta strandi489 – 491Combined sources3
Helixi494 – 502Combined sources9
Helixi508 – 517Combined sources10
Helixi520 – 524Combined sources5
Beta strandi529 – 531Combined sources3
Helixi535 – 537Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4TNBX-ray2.11A1-590[»]
4TNDX-ray1.80A1-590[»]
ProteinModelPortaliP34947.
SMRiP34947.
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 calmodulinAdd BLAST20
Regioni546 – 565Sufficient for membrane localizationAdd BLAST20

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi388 – 395Nuclear localization signal1 Publication8

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.
InParanoidiP34947.
KOiK08291.
OMAiEFENSMY.
OrthoDBiEOG091G062G.
PhylomeDBiP34947.
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.

P34947-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MELENIVANT VLLKAREGGG GKRKGKSKKW KEILKFPHIS QCEDLRRTID
60 70 80 90 100
RDYCSLCDKQ PIGRLLFRQF CETRPGLECY IQFLDSVAEY EVTPDEKLGE
110 120 130 140 150
KGKEIMTKYL TPKSPVFIAQ VGQDLVSQTE EKLLQKPCKE LFSACAQSVH
160 170 180 190 200
EYLRGEPFHE YLDSMFFDRF 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
VLETEEVYSH KFSEEAKSIC KMLLTKDAKQ RLGCQEEGAA EVKRHPFFRN
460 470 480 490 500
MNFKRLEAGM LDPPFVPDPR AVYCKDVLDI EQFSTVKGVN LDHTDDDFYS
510 520 530 540 550
KFSTGSVSIP WQNEMIETEC FKELNVFGPN GTLPPDLNRN HPPEPPKKGL
560 570 580 590
LQRLFKRQHQ NNSKSSPSSK TSFNHHINSN HVSSNSTGSS
Length:590
Mass (Da):67,787
Last modified:February 1, 1994 - v1
Checksum:iD363567ECFF5CF21
GO

Polymorphismi

Variant Leu-41 variant is rare in European-Americans individuals but common in African-Americans individuals (40% of the African-American individuals studied carry at least one allele). Variant leu-41 is associated with decreased mortality in African-Americans with heart failure or cardiac ischemia.

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04051741Q → L Exerts a protective effect in heart failure and ischemia. 2 PublicationsCorresponds to variant rs2230345dbSNPEnsembl.1
Natural variantiVAR_040518119A → V.1 PublicationCorresponds to variant rs55980792dbSNPEnsembl.1
Natural variantiVAR_040519122G → S.1 PublicationCorresponds to variant rs55902633dbSNPEnsembl.1
Natural variantiVAR_040520129T → M.1 PublicationCorresponds to variant rs34679178dbSNPEnsembl.1
Natural variantiVAR_040521141L → I.1 PublicationCorresponds to variant rs56254855dbSNPEnsembl.1
Natural variantiVAR_040522163D → E in a lung neuroendocrine carcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_059766172Q → H.Corresponds to variant rs45630572dbSNPEnsembl.1
Natural variantiVAR_040523304R → H.1 PublicationCorresponds to variant rs2230349dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L15388 mRNA. Translation: AAA58620.1.
AL355273, AL355861, AL583824 Genomic DNA. Translation: CAI16487.1.
AL355861, AL355273, AL583824 Genomic DNA. Translation: CAI15804.1.
AL583824, AL355273, AL355861 Genomic DNA. Translation: CAI16759.1.
CH471066 Genomic DNA. Translation: EAW49394.1.
CH471066 Genomic DNA. Translation: EAW49395.1.
BC064506 mRNA. Translation: AAH64506.1.
CCDSiCCDS7612.1.
PIRiA48277.
B48682.
RefSeqiNP_005299.1. NM_005308.2.
UniGeneiHs.524625.
Hs.736460.

Genome annotation databases

EnsembliENST00000392870; ENSP00000376609; ENSG00000198873.
GeneIDi2869.
KEGGihsa:2869.
UCSCiuc001led.4. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L15388 mRNA. Translation: AAA58620.1.
AL355273, AL355861, AL583824 Genomic DNA. Translation: CAI16487.1.
AL355861, AL355273, AL583824 Genomic DNA. Translation: CAI15804.1.
AL583824, AL355273, AL355861 Genomic DNA. Translation: CAI16759.1.
CH471066 Genomic DNA. Translation: EAW49394.1.
CH471066 Genomic DNA. Translation: EAW49395.1.
BC064506 mRNA. Translation: AAH64506.1.
CCDSiCCDS7612.1.
PIRiA48277.
B48682.
RefSeqiNP_005299.1. NM_005308.2.
UniGeneiHs.524625.
Hs.736460.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4TNBX-ray2.11A1-590[»]
4TNDX-ray1.80A1-590[»]
ProteinModelPortaliP34947.
SMRiP34947.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109127. 172 interactors.
DIPiDIP-57457N.
IntActiP34947. 2 interactors.
MINTiMINT-3013589.
STRINGi9606.ENSP00000376609.

Chemistry databases

BindingDBiP34947.
ChEMBLiCHEMBL5678.
GuidetoPHARMACOLOGYi1469.

PTM databases

iPTMnetiP34947.
PhosphoSitePlusiP34947.

Polymorphism and mutation databases

BioMutaiGRK5.
DMDMi462203.

Proteomic databases

MaxQBiP34947.
PaxDbiP34947.
PeptideAtlasiP34947.
PRIDEiP34947.

Protocols and materials databases

DNASUi2869.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000392870; ENSP00000376609; ENSG00000198873.
GeneIDi2869.
KEGGihsa:2869.
UCSCiuc001led.4. human.

Organism-specific databases

CTDi2869.
DisGeNETi2869.
GeneCardsiGRK5.
HGNCiHGNC:4544. GRK5.
HPAiCAB025579.
HPA046838.
MIMi600870. gene.
neXtProtiNX_P34947.
OpenTargetsiENSG00000198873.
PharmGKBiPA180.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0986. Eukaryota.
ENOG410YRQZ. LUCA.
GeneTreeiENSGT00860000133699.
HOGENOMiHOG000006742.
HOVERGENiHBG004532.
InParanoidiP34947.
KOiK08291.
OMAiEFENSMY.
OrthoDBiEOG091G062G.
PhylomeDBiP34947.
TreeFamiTF313940.

Enzyme and pathway databases

BioCyciZFISH:HS01823-MONOMER.
BRENDAi2.7.11.16. 2681.
ReactomeiR-HSA-416476. G alpha (q) signalling events.
R-HSA-418555. G alpha (s) signalling events.
SignaLinkiP34947.
SIGNORiP34947.

Miscellaneous databases

ChiTaRSiGRK5. human.
GeneWikiiGRK5.
GenomeRNAii2869.
PROiP34947.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000198873.
CleanExiHS_GRK5.
GenevisibleiP34947. HS.

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_HUMAN
AccessioniPrimary (citable) accession number: P34947
Secondary accession number(s): D3DRD0, Q5T059
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 1, 1994
Last sequence update: February 1, 1994
Last modified: November 30, 2016
This is version 167 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 10
    Human chromosome 10: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. 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.