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Protein

G protein-coupled receptor kinase 5

Gene

GRK5

Organism
Bos taurus (Bovine)
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 (Beta-2 adrenergic receptor), 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) (By similarity).By similarity

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

BRENDAi2.7.11.16. 908.
ReactomeiREACT_209521. 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
OrganismiBos taurus (Bovine)
Taxonomic identifieri9913 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
ProteomesiUP000009136: Chromosome 26

Subcellular locationi

Cytoplasm By similarity. Nucleus By similarity. Cell membrane By similarity; Peripheral membrane protein By similarity
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
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 590590G protein-coupled receptor kinase 5PRO_0000085970Add
BLAST

Amino acid modifications

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

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

PRIDEiP43249.

Expressioni

Tissue specificityi

Highest levels in lung, heart, retina, lingual epithelium. Very little in brain, liver, kidney.1 Publication

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

Protein-protein interaction databases

DIPiDIP-60782N.
STRINGi9913.ENSBTAP00000010492.

Structurei

3D structure databases

ProteinModelPortaliP43249.
SMRiP43249. Positions 23-532.
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.
GeneTreeiENSGT00770000120493.
HOGENOMiHOG000006742.
HOVERGENiHBG004532.
InParanoidiP43249.
KOiK08291.
OMAiNFYTKFN.
OrthoDBiEOG7V1FQK.
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.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[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.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50132. RGS. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P43249-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MELENIVANT VLLKAREGGG GKRKGKSKKW KEILKFPHIN QCEDLRRTID
60 70 80 90 100
RDYCSLCDKQ PVGRLLFRQF CETRPGLESY IQFLDSVAEY EVTPDEKLGE
110 120 130 140 150
KGKEIMTKYL TPKSPVFITQ VGRDLVSQTE EKLLQKPCKE LFSACVQSVH
160 170 180 190 200
DYLRGEPFHE YLDSMYFDRF LQWKWLERQP VTKNTFRQYR VLGKGGFGEV
210 220 230 240 250
CACQVRATGK MYACKRLEKK RIKKRKGESM ALNEKQILEK VNSRFVVNLA
260 270 280 290 300
YAYETKDALC LVLTIMNGGD LKFHIYNMGN PGFEEERALF YAAEILCGLE
310 320 330 340 350
DLHHENIVYR 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
KFSTGSVPIP WQSEMIETEC FKELNVFGPH GTLSPDLNRS HPPEPPKKGL
560 570 580 590
LQRLFKRQHQ NNSKSSPNSK TSFNHHINSN HVSSNSTGSS
Length:590
Mass (Da):67,889
Last modified:November 1, 1995 - v1
Checksum:iE8F353697D8BA6E2
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U01206 mRNA. Translation: AAA17561.1.
PIRiA54372.
RefSeqiNP_776756.1. NM_174331.2.
UniGeneiBt.4263.

Genome annotation databases

EnsembliENSBTAT00000010492; ENSBTAP00000010492; ENSBTAG00000007981.
GeneIDi281801.
KEGGibta:281801.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U01206 mRNA. Translation: AAA17561.1.
PIRiA54372.
RefSeqiNP_776756.1. NM_174331.2.
UniGeneiBt.4263.

3D structure databases

ProteinModelPortaliP43249.
SMRiP43249. Positions 23-532.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

DIPiDIP-60782N.
STRINGi9913.ENSBTAP00000010492.

Proteomic databases

PRIDEiP43249.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSBTAT00000010492; ENSBTAP00000010492; ENSBTAG00000007981.
GeneIDi281801.
KEGGibta:281801.

Organism-specific databases

CTDi2869.

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00770000120493.
HOGENOMiHOG000006742.
HOVERGENiHBG004532.
InParanoidiP43249.
KOiK08291.
OMAiNFYTKFN.
OrthoDBiEOG7V1FQK.
TreeFamiTF313940.

Enzyme and pathway databases

BRENDAi2.7.11.16. 908.
ReactomeiREACT_209521. G alpha (q) signalling events.

Miscellaneous databases

NextBioi20805714.

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.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[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.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50132. RGS. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "Identification, purification, and characterization of GRK5, a member of the family of G protein-coupled receptor kinases."
    Premont R.T., Koch W.J., Inglese J., Lefkowitz R.J.
    J. Biol. Chem. 269:6832-6841(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 479-491, TISSUE SPECIFICITY, FUNCTION, AUTOPHOSPHORYLATION.
    Tissue: Tongue epithelium.

Entry informationi

Entry nameiGRK5_BOVIN
AccessioniPrimary (citable) accession number: P43249
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: November 1, 1995
Last modified: January 7, 2015
This is version 109 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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 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.