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Reviewed, UniProtKB/Swiss-Prot P32298 (GRK4_HUMAN)

Last modified November 3, 2009. Version 104. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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) [Complete proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length578 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
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 heparine. 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 co-localization with DRD3 is observed strongly at 5 and 15 minutes. DRD3 and GRK4 co-localize in lipid rafts of renal proximal tubule cells. Ref.3 Ref.9

Tissue specificity

Testis, and in a lower extent in other tissues including brain cortex and striatum. Has a widespread but low level of expression. Also expressed in myometrium; namely the GRK4-gamma isoform. 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

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: dbSNP rs2960306. Ref.10
VAR_024573
Natural variant951D → H: dbSNP rs13305979.
VAR_051621
Natural variant1161A → T: dbSNP rs34857805. Ref.10
VAR_046043
Natural variant1421A → V: dbSNP rs1024323. Ref.10
VAR_024574
Natural variant1831T → R: dbSNP rs45538934.
VAR_051622
Natural variant2471V → I: dbSNP rs35605687. Ref.10
VAR_007806
Natural variant3831H → Q
VAR_046044
Natural variant4251L → P
VAR_040516
Natural variant4401A → V: dbSNP rs1801058.
VAR_051623
Natural variant4731V → I
VAR_046045
Natural variant4861V → A: dbSNP rs1801058. Ref.3 Ref.10 Ref.1 Ref.2 Ref.4 Ref.7
VAR_024575
Natural variant4951A → T
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).

Checksum: AD60D125A5839CA3
Show »

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

Checksum: 6AF0953E8D1F7A06
Show »

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

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: 1338872] [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: 9092566] [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: 8626439] [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: 8135832] [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: 15815621] [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: 15489334] [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: 16636192] [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: 19520868] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, SUBCELLULAR LOCATION, INTERACTION WITH DRD3.
[10]"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: 17344846] [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

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.
IPIIPI00180426.
IPI00182614.
IPI00217944.
IPI00337306.
PIRI54326.
JC2127.
RefSeqNP_001004056.1.
NP_001004057.1.
NP_892027.2.
UniGeneHs.32959

3D structure databases

ModBaseSearch...

Protein-protein interaction databases

STRINGP32298.

Proteomic databases

PRIDEP32298.

Genome annotation databases

EnsemblENST00000345167; ENSP00000264764; ENSG00000125388; Homo sapiens. [Genome view]
ENST00000398047; ENSP00000381125; ENSG00000125388; Homo sapiens. [Genome view]
ENST00000398051; ENSP00000381128; ENSG00000125388; Homo sapiens. [Genome view]
ENST00000398052; ENSP00000381129; ENSG00000125388; Homo sapiens. [Genome view]
ENST00000442472; ENSP00000392297; ENSG00000125388; Homo sapiens. [Genome view]
ENST00000446963; ENSP00000396463; ENSG00000125388; Homo sapiens. [Genome view]
GeneID2868.
KEGGhsa:2868.
NMPDRfig|9606.3.peg.23842.
UCSCuc003ggn.1. human.
uc003ggo.1. human.
uc003ggp.1. human.
uc003ggq.1. human.

Organism-specific databases

CTD2868.
GeneCardsGC04P003002.
H-InvDBHIX0031441.
HGNCHGNC:4543. GRK4.
HPACAB004421.
MIM137026. gene.
PharmGKBPA28941.
GenAtlasSearch...

Phylogenomic databases

HOVERGENP32298.

Enzyme and pathway databases

BRENDA2.7.11.16. 247.

Gene expression databases

ArrayExpressP32298.
BgeeP32298.
GenevestigatorP32298.
GermOnlineENSG00000125388. Homo sapiens.

Family and domain databases

InterProIPR000961. AGC-kinase_C.
IPR000239. GPCR_kinase.
IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_BS.
IPR000342. Regulat_G_prot_signal.
IPR017442. Se/Thr_pkinase-rel.
IPR008271. Ser_thr_pkin_AS.
IPR002290. Ser_thr_pkinase.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
PF00615. RGS. 1 hit.
[Graphical view]
PRINTSPR00717. GPCRKINASE.
ProDomPD000001. Prot_kinase. 1 hit.
[Graphical view] [Entries sharing at least one domain]
SMARTSM00315. RGS. 1 hit.
SM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
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 Resources

NextBio11309.
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: November 3, 2009
This is version 104 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)
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.

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SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents