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P32298 (GRK4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 144. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
G protein-coupled receptor kinase 4

EC=2.7.11.16
Alternative name(s):
G protein-coupled receptor kinase GRK4
ITI1
Gene names
Name:GRK4
Synonyms:GPRK2L, GPRK4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length578 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Specifically phosphorylates the activated forms of G protein-coupled receptors. GRK4-alpha can phosphorylate rhodopsin and its activity is inhibited by calmodulin; the other three isoforms do not phosphorylate rhodopsin and do not interact with calmodulin. GRK4-alpha and GRK4-gamma phosphorylate DRD3. Phosphorylates ADRB2. Ref.3 Ref.9

Catalytic activity

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

Enzyme regulation

Inhibited by heparin. Ref.9

Subunit structure

Interacts with DRD3. Ref.9

Subcellular location

Cytoplasm. Cytoplasmcell cortex. Note: Both at the cell surface and dispersed in the cytoplasm under basal conditions. Receptor stimulation results in the internalization of GRK4 to the perinuclear area, where colocalization with DRD3 is observed strongly at 5 and 15 minutes. DRD3 and GRK4 colocalize in lipid rafts of renal proximal tubule cells. Ref.3 Ref.9

Tissue specificity

Isoform 1, isoform 2, isoform 3, and isoform 4 are expressed in testis. Isoform 4 is expressed in myometrium. Ref.3 Ref.8

Post-translational modification

Palmitoylated. Ref.3

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.

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P32298-1)

Also known as: GRK4-alpha; GRK4D;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P32298-2)

Also known as: GRK4-beta; GRK4C;

The sequence of this isoform differs from the canonical sequence as follows:
     18-49: Missing.
Isoform 3 (identifier: P32298-3)

Also known as: GRK4-delta; GRK4A;

The sequence of this isoform differs from the canonical sequence as follows:
     18-49: Missing.
     516-561: Missing.
Isoform 4 (identifier: P32298-4)

Also known as: GRK4-gamma; GRK4B;

The sequence of this isoform differs from the canonical sequence as follows:
     516-561: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 578578G protein-coupled receptor kinase 4
PRO_0000085967

Regions

Domain52 – 172121RGS
Domain187 – 449263Protein kinase
Domain450 – 51566AGC-kinase C-terminal
Nucleotide binding193 – 2019ATP By similarity
Region1 – 154154N-terminal

Sites

Active site3121Proton acceptor By similarity
Binding site2161ATP By similarity

Amino acid modifications

Modified residue11N-acetylmethionine Ref.10

Natural variations

Alternative sequence18 – 4932Missing in isoform 2 and isoform 3.
VSP_004936
Alternative sequence516 – 56146Missing in isoform 3 and isoform 4.
VSP_004937
Natural variant651R → L. Ref.11
Corresponds to variant rs2960306 [ dbSNP | Ensembl ].
VAR_024573
Natural variant951D → H.
Corresponds to variant rs13305979 [ dbSNP | Ensembl ].
VAR_051621
Natural variant1161A → T. Ref.11
Corresponds to variant rs34857805 [ dbSNP | Ensembl ].
VAR_046043
Natural variant1421A → V. Ref.11
Corresponds to variant rs1024323 [ dbSNP | Ensembl ].
VAR_024574
Natural variant1831T → R.
Corresponds to variant rs45538934 [ dbSNP | Ensembl ].
VAR_051622
Natural variant2471V → I. Ref.11
Corresponds to variant rs35605687 [ dbSNP | Ensembl ].
VAR_007806
Natural variant3831H → Q. Ref.11
Corresponds to variant rs55852353 [ dbSNP | Ensembl ].
VAR_046044
Natural variant4251L → P. Ref.11
VAR_040516
Natural variant4401A → V.
Corresponds to variant rs1801058 [ dbSNP | Ensembl ].
VAR_051623
Natural variant4731V → I. Ref.11
Corresponds to variant rs35024854 [ dbSNP | Ensembl ].
VAR_046045
Natural variant4861V → A. Ref.1 Ref.2 Ref.3 Ref.4 Ref.7 Ref.11
Corresponds to variant rs1801058 [ dbSNP | Ensembl ].
VAR_024575
Natural variant4951A → T. Ref.11
Corresponds to variant rs35463176 [ dbSNP | Ensembl ].
VAR_046046

Experimental info

Sequence conflict5621G → D in CAA66468. Ref.1
Sequence conflict5621G → D in CAA66802. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (GRK4-alpha) (GRK4D) [UniParc].

Last modified April 3, 2007. Version 3.
Checksum: 72FCF94ED551F2D0

FASTA57866,583
        10         20         30         40         50         60 
MELENIVANS LLLKARQGGY GKKSGRSKKW KEILTLPPVS QCSELRHSIE KDYSSLCDKQ 

        70         80         90        100        110        120 
PIGRRLFRQF CDTKPTLKRH IEFLDAVAEY EVADDEDRSD CGLSILDRFF NDKLAAPLPE 

       130        140        150        160        170        180 
IPPDVVTECR LGLKEENPSK KAFEECTRVA HNYLRGEPFE EYQESSYFSQ FLQWKWLERQ 

       190        200        210        220        230        240 
PVTKNTFRHY RVLGKGGFGE VCACQVRATG KMYACKKLQK KRIKKRKGEA MALNEKRILE 

       250        260        270        280        290        300 
KVQSRFVVSL AYAYETKDAL CLVLTIMNGG DLKFHIYNLG NPGFDEQRAV FYAAELCCGL 

       310        320        330        340        350        360 
EDLQRERIVY RDLKPENILL DDRGHIRISD LGLATEIPEG QRVRGRVGTV GYMAPEVVNN 

       370        380        390        400        410        420 
EKYTFSPDWW GLGCLIYEMI QGHSPFKKYK EKVKWEEVDQ RIKNDTEEYS EKFSEDAKSI 

       430        440        450        460        470        480 
CRMLLTKNPS KRLGCRGEGA AGVKQHPVFK DINFRRLEAN MLEPPFCPDP HAVYCKDVLD 

       490        500        510        520        530        540 
IEQFSVVKGI YLDTADEDFY ARFATGCVSI PWQNEMIESG CFKDINKSES EEALPLDLDK 

       550        560        570 
NIHTPVSRPN RGFFYRLFRR GGCLTMVPSE KEVEPKQC 

« Hide

Isoform 2 (GRK4-beta) (GRK4C) [UniParc].

Checksum: AD60D125A5839CA3
Show »

FASTA54663,030
Isoform 3 (GRK4-delta) (GRK4A) [UniParc].

Checksum: 6AF0953E8D1F7A06
Show »

FASTA50057,663
Isoform 4 (GRK4-gamma) (GRK4B) [UniParc].

Checksum: 1DD49402FCB381E5
Show »

FASTA53261,216

References

« Hide 'large scale' references
[1]"A novel G protein-coupled receptor kinase gene cloned from 4p16.3."
Ambrose C., James M., Barnes G., Lin C., Bates G., Altherr M., Duyao M., Groot N., Church D., Wasmuth J.J., Lehrach H., Housman D., Buckler A.J., Gusella J.F., McDonald M.E.
Hum. Mol. Genet. 1:697-703(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 3), VARIANT ALA-486.
[2]"G protein-coupled receptor kinase GRK4. Molecular analysis of the four isoforms and ultrastructural localization in spermatozoa and germinal cells."
Sallese M., Mariggio S., Collodel G., Moretti E., Piomboni P., Baccetti B., de Blasi A.
J. Biol. Chem. 272:10188-10195(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4), VARIANT ALA-486.
Tissue: Testis.
[3]"Characterization of the G protein-coupled receptor kinase GRK4. Identification of four splice variants."
Premont R.T., Macrae A.D., Stoffel R.H., Chung N., Pitcher J.A., Ambrose C., Inglese J., MacDonald M.E., Lefkowitz R.J.
J. Biol. Chem. 271:6403-6410(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], ALTERNATIVE SPLICING, FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, PALMITOYLATION, VARIANT ALA-486.
Tissue: Testis.
[4]"Two isoforms of G protein-coupled receptor kinase 4 identified by molecular cloning."
Sallese M., Lombardi M.S., de Blasi A.
Biochem. Biophys. Res. Commun. 199:848-854(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), VARIANT ALA-486.
Tissue: Brain.
[5]Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.
Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
Tissue: Kidney.
[6]"Generation and annotation of the DNA sequences of human chromosomes 2 and 4."
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. expand/collapse author list , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K.
Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]"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] (ISOFORM 1), VARIANT ALA-486.
[8]"Amelioration of genetic hypertension by suppression of renal G protein-coupled receptor kinase type 4 expression."
Sanada H., Yatabe J., Midorikawa S., Katoh T., Hashimoto S., Watanabe T., Xu J., Luo Y., Wang X., Zeng C., Armando I., Felder R.A., Jose P.A.
Hypertension 47:1131-1139(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[9]"G protein-coupled receptor kinase 4 (GRK4) regulates the phosphorylation and function of the dopamine D3 receptor."
Villar V.A.M., Jones J.E., Armando I., Palmes-Saloma C., Yu P., Pascua A.M., Keever L., Arnaldo F.B., Wang Z., Luo Y., Felder R.A., Jose P.A.
J. Biol. Chem. 284:21425-21434(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION, INTERACTION WITH DRD3.
[10]"Comparative large-scale characterisation of plant vs. mammal proteins reveals similar and idiosyncratic N-alpha acetylation features."
Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., Giglione C.
Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] LEU-65; THR-116; VAL-142; ILE-247; GLN-383; PRO-425; ILE-473; ALA-486 AND THR-495.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L03718 Genomic DNA. Translation: AAB04045.1.
X97879 mRNA. Translation: CAA66468.1.
X97880 mRNA. Translation: CAA66469.1.
X97881 mRNA. Translation: CAA66470.1.
U33054 mRNA. Translation: AAC50406.1.
U33055 mRNA. Translation: AAC50407.1.
U33056 mRNA. Translation: AAC50408.1.
U33168 expand/collapse EMBL AC list , U33153, U33155, U33156, U33157, U33158, U33159, U33160, U33161, U33162, U33163, U33164, U33165, U33166, U33167 Genomic DNA. Translation: AAC50409.1.
U33168 expand/collapse EMBL AC list , U33153, U33154, U33155, U33156, U33157, U33158, U33159, U33160, U33161, U33162, U33163, U33164, U33165, U33166, U33167 Genomic DNA. Translation: AAC50410.1.
U33168 expand/collapse EMBL AC list , U33153, U33154, U33155, U33156, U33157, U33158, U33159, U33160, U33161, U33162, U33163, U33164, U33165, U33166 Genomic DNA. Translation: AAC50411.1.
U33168 expand/collapse EMBL AC list , U33153, U33155, U33156, U33157, U33158, U33159, U33160, U33161, U33162, U33163, U33164, U33165, U33166 Genomic DNA. Translation: AAC50412.1.
AK223581 mRNA. Translation: BAD97301.1.
X98118 mRNA. Translation: CAA66802.1.
X75897 mRNA. Translation: CAA53506.1.
Z68192 Genomic DNA. Translation: CAA92341.1.
BC117320 mRNA. Translation: AAI17321.1.
PIRI54326.
JC2127.
RefSeqNP_001004056.1. NM_001004056.1.
NP_001004057.1. NM_001004057.1.
NP_005298.2. NM_005307.2.
NP_892027.2. NM_182982.2.
UniGeneHs.32959.

3D structure databases

ProteinModelPortalP32298.
SMRP32298. Positions 2-558.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109126. 6 interactions.
IntActP32298. 2 interactions.

Chemistry

BindingDBP32298.
ChEMBLCHEMBL5861.
GuidetoPHARMACOLOGY1468.

PTM databases

PhosphoSiteP32298.

Polymorphism databases

DMDM143811400.

Proteomic databases

PaxDbP32298.
PRIDEP32298.

Protocols and materials databases

DNASU2868.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000345167; ENSP00000264764; ENSG00000125388. [P32298-2]
ENST00000398051; ENSP00000381128; ENSG00000125388. [P32298-3]
ENST00000398052; ENSP00000381129; ENSG00000125388. [P32298-1]
ENST00000504933; ENSP00000427445; ENSG00000125388. [P32298-4]
GeneID2868.
KEGGhsa:2868.
UCSCuc003ggn.1. human. [P32298-1]
uc003ggo.1. human. [P32298-4]
uc003ggp.1. human. [P32298-2]
uc003ggq.1. human. [P32298-3]

Organism-specific databases

CTD2868.
GeneCardsGC04P002967.
HGNCHGNC:4543. GRK4.
HPACAB004421.
HPA028737.
MIM137026. gene.
neXtProtNX_P32298.
PharmGKBPA28941.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOVERGENHBG004532.
KOK08291.
OMAHSIEKDY.
OrthoDBEOG7V1FQK.
PhylomeDBP32298.
TreeFamTF313940.

Enzyme and pathway databases

BRENDA2.7.11.16. 2681.
SignaLinkP32298.

Gene expression databases

ArrayExpressP32298.
BgeeP32298.
GenevestigatorP32298.

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.
IPR008271. Ser/Thr_kinase_AS.
[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.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS50132. RGS. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiGRK4.
GenomeRNAi2868.
NextBio11309.
PROP32298.
SOURCESearch...

Entry information

Entry nameGRK4_HUMAN
AccessionPrimary (citable) accession number: P32298
Secondary accession number(s): O00641 expand/collapse secondary AC list , O00642, Q13293, Q13294, Q13295, Q14453, Q14725, Q15313, Q15314, Q15315, Q15316, Q17RH6, Q53EQ8
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1993
Last sequence update: April 3, 2007
Last modified: April 16, 2014
This is version 144 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 4

Human chromosome 4: entries, gene names and cross-references to MIM