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P43250 (GRK6_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 149. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
G protein-coupled receptor kinase 6

EC=2.7.11.16
Alternative name(s):
G protein-coupled receptor kinase GRK6
Gene names
Name:GRK6
Synonyms:GPRK6
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length576 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Specifically phosphorylates the activated forms of G protein-coupled receptors. Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their desensitization. Seems to be involved in the desensitization of D2-like dopamine receptors in striatum and chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis By similarity. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor: LRP6 during Wnt signaling (in vitro). Ref.8 Ref.10

Catalytic activity

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

Subcellular location

Membrane; Lipid-anchor.

Tissue specificity

Widely expressed. Ref.5

Post-translational modification

It is uncertain whether palmitoylation is on Cys-561 and/or Cys-562 and/or Cys-565. Ref.6

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.

Binary interactions

With

Entry

#Exp.

IntAct

Notes

ROM1P522059EBI-722747,EBI-8176947From a different organism.

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform GRK6A (identifier: P43250-1)

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 GRK6B (identifier: P43250-2)

The sequence of this isoform differs from the canonical sequence as follows:
     560-576: DCCGNCSDSEEELPTRL → RIAVETAATARKSSPPASSPQPEAPTSSWR
Isoform GRK6C (identifier: P43250-3)

The sequence of this isoform differs from the canonical sequence as follows:
     560-560: D → R
     561-576: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 576576G protein-coupled receptor kinase 6
PRO_0000085974

Regions

Domain53 – 171119RGS
Domain186 – 448263Protein kinase
Domain449 – 51466AGC-kinase C-terminal
Nucleotide binding192 – 2009ATP
Nucleotide binding264 – 2707ATP
Nucleotide binding315 – 3184ATP
Region1 – 185185N-terminal

Sites

Active site3111Proton acceptor By similarity
Binding site2151ATP

Amino acid modifications

Modified residue4841Phosphoserine Ref.7 Ref.9
Modified residue4851Phosphothreonine Ref.7 Ref.9
Lipidation5611S-palmitoyl cysteine Probable
Lipidation5621S-palmitoyl cysteine Probable
Lipidation5651S-palmitoyl cysteine Probable

Natural variations

Alternative sequence560 – 57617DCCGN…LPTRL → RIAVETAATARKSSPPASSP QPEAPTSSWR in isoform GRK6B.
VSP_004938
Alternative sequence5601D → R in isoform GRK6C.
VSP_041813
Alternative sequence561 – 57616Missing in isoform GRK6C.
VSP_041814
Natural variant311R → Q in a gastric adenocarcinoma sample; somatic mutation. Ref.13
VAR_040524
Natural variant731T → M. Ref.13
Corresponds to variant rs56382815 [ dbSNP | Ensembl ].
VAR_040525
Natural variant2751I → M in a breast infiltrating ductal carcinoma sample; somatic mutation. Ref.13
VAR_040526

Experimental info

Mutagenesis61I → A: 12-13 fold defects in kinase activity; 180-fold defects in kinase activity; when associated with A-7. Ref.12
Mutagenesis71V → A: 12-13 fold defects in kinase activity; 180-fold defects in kinase activity; when associated with A-6. Ref.12
Mutagenesis91N → A: 140-fold defects in kinase activity. Ref.12
Mutagenesis121L → A: 1100-fold defects in kinase activity. Ref.12
Mutagenesis5611C → S: Abolishes palmitoylation; when associated with S-562 and S-565. Ref.6
Mutagenesis5621C → S: Abolishes palmitoylation; when associated with S-561 and S-565. Ref.6
Mutagenesis5651C → S: Abolishes palmitoylation; when associated with S-561 and S-562. Ref.6
Sequence conflict60 – 612QP → HA in AAA60175. Ref.1
Sequence conflict104 – 1052QL → HV in AAA60175. Ref.1

Secondary structure

............................................................................................... 576
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform GRK6A [UniParc].

Last modified January 23, 2002. Version 2.
Checksum: 3BF8C3B1CDE2BD74

FASTA57665,991
        10         20         30         40         50         60 
MELENIVANT VLLKAREGGG GNRKGKSKKW RQMLQFPHIS QCEELRLSLE RDYHSLCERQ 

        70         80         90        100        110        120 
PIGRLLFREF CATRPELSRC VAFLDGVAEY EVTPDDKRKA CGRQLTQNFL SHTGPDLIPE 

       130        140        150        160        170        180 
VPRQLVTNCT QRLEQGPCKD LFQELTRLTH EYLSVAPFAD YLDSIYFNRF LQWKWLERQP 

       190        200        210        220        230        240 
VTKNTFRQYR VLGKGGFGEV CACQVRATGK MYACKKLEKK RIKKRKGEAM ALNEKQILEK 

       250        260        270        280        290        300 
VNSRFVVSLA YAYETKDALC LVLTLMNGGD LKFHIYHMGQ AGFPEARAVF YAAEICCGLE 

       310        320        330        340        350        360 
DLHRERIVYR DLKPENILLD DHGHIRISDL GLAVHVPEGQ TIKGRVGTVG YMAPEVVKNE 

       370        380        390        400        410        420 
RYTFSPDWWA LGCLLYEMIA GQSPFQQRKK KIKREEVERL VKEVPEEYSE RFSPQARSLC 

       430        440        450        460        470        480 
SQLLCKDPAE RLGCRGGSAR EVKEHPLFKK LNFKRLGAGM LEPPFKPDPQ AIYCKDVLDI 

       490        500        510        520        530        540 
EQFSTVKGVE LEPTDQDFYQ KFATGSVPIP WQNEMVETEC FQELNVFGLD GSVPPDLDWK 

       550        560        570 
GQPPAPPKKG LLQRLFSRQD CCGNCSDSEE ELPTRL 

« Hide

Isoform GRK6B [UniParc].

Checksum: BD7C24E9624DDFEC
Show »

FASTA58967,257
Isoform GRK6C [UniParc].

Checksum: 2686CECDFC7B3516
Show »

FASTA56064,294

References

« Hide 'large scale' references
[1]"Molecular cloning and expression of GRK6. A new member of the G protein-coupled receptor kinase family."
Benovic J.L., Gomez J.
J. Biol. Chem. 268:19521-19527(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM GRK6A).
[2]"The GRK4 subfamily of G protein-coupled receptor kinases. Alternative splicing, gene organization, and sequence conservation."
Premont R.T., Macrae A.D., Aparicio S.A., Kendall H.E., Welch J.E., Lefkowitz R.J.
J. Biol. Chem. 274:29381-29389(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS GRK6B AND GRK6C).
[3]"The DNA sequence and comparative analysis of human chromosome 5."
Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S. expand/collapse author list , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.
Nature 431:268-274(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"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 GRK6A).
Tissue: Uterus.
[5]"Identification of additional members of human G-protein-coupled receptor kinase multigene family."
Haribabu B., Snyderman R.
Proc. Natl. Acad. Sci. U.S.A. 90:9398-9402(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 33-576, TISSUE SPECIFICITY.
[6]"Palmitoylation of G protein-coupled receptor kinase, GRK6. Lipid modification diversity in the GRK family."
Stoffel R.H., Randall R.R., Premont R.T., Lefkowitz R.J., Inglese J.
J. Biol. Chem. 269:27791-27794(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: PALMITOYLATION AT CYS-561; CYS-562 AND CYS-565, MUTAGENESIS OF CYS-561; CYS-562 AND CYS-565.
[7]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-484 AND THR-485, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[8]"G Protein-coupled receptor kinases phosphorylate LRP6 in the Wnt pathway."
Chen M., Philipp M., Wang J., Premont R.T., Garrison T.R., Caron M.G., Lefkowitz R.J., Chen W.
J. Biol. Chem. 284:35040-35048(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF LRP6.
[9]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-484 AND THR-485, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[10]"Site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases and results in differential modulation of CXCR4 signaling."
Busillo J.M., Armando S., Sengupta R., Meucci O., Bouvier M., Benovic J.L.
J. Biol. Chem. 285:7805-7817(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF CXCR4.
[11]"The structure of G protein-coupled receptor kinase (GRK)-6 defines a second lineage of GRKs."
Lodowski D.T., Tesmer V.M., Benovic J.L., Tesmer J.J.
J. Biol. Chem. 281:16785-16793(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
[12]"Molecular basis for activation of G protein-coupled receptor kinases."
Boguth C.A., Singh P., Huang C.C., Tesmer J.J.
EMBO J. 29:3249-3259(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.72 ANGSTROMS) IN COMPLEX WITH AMP AND SANGIVAMYCIN, MUTAGENESIS OF ILE-6; VAL-7; ASN-9 AND LEU-12.
[13]"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] GLN-31; MET-73 AND MET-275.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L16862 mRNA. Translation: AAA60175.1.
AF040751 mRNA. Translation: AAC09273.1.
AF040752 mRNA. Translation: AAC09274.1.
AC145098 Genomic DNA. No translation available.
BC009277 mRNA. Translation: AAH09277.1.
U00686 mRNA. Translation: AAA03565.1.
PIRA48765.
RefSeqNP_001004105.1. NM_001004105.2.
NP_001004106.1. NM_001004106.2.
NP_002073.2. NM_002082.3.
UniGeneHs.235116.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2ACXX-ray2.60A/B1-576[»]
3NYNX-ray2.72A/B2-576[»]
3NYOX-ray2.92A/B2-576[»]
ProteinModelPortalP43250.
SMRP43250. Positions 2-557.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109128. 15 interactions.
IntActP43250. 4 interactions.
MINTMINT-1425525.
STRING9606.ENSP00000377204.

Chemistry

BindingDBP43250.
ChEMBLCHEMBL6144.
GuidetoPHARMACOLOGY1470.

PTM databases

PhosphoSiteP43250.

Polymorphism databases

DMDM20141386.

Proteomic databases

PaxDbP43250.
PRIDEP43250.

Protocols and materials databases

DNASU2870.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000355472; ENSP00000347655; ENSG00000198055. [P43250-1]
ENST00000355958; ENSP00000348230; ENSG00000198055. [P43250-3]
ENST00000528793; ENSP00000433511; ENSG00000198055. [P43250-2]
GeneID2870.
KEGGhsa:2870.
UCSCuc003mgq.2. human. [P43250-3]
uc021yit.1. human. [P43250-1]
uc021yiu.1. human. [P43250-2]

Organism-specific databases

CTD2870.
GeneCardsGC05P176853.
HGNCHGNC:4545. GRK6.
HPAHPA015327.
HPA018903.
MIM600869. gene.
neXtProtNX_P43250.
PharmGKBPA28942.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000006742.
HOVERGENHBG004532.
KOK08291.
OMAMLEPPFK.
OrthoDBEOG7V1FQK.
PhylomeDBP43250.
TreeFamTF313940.

Enzyme and pathway databases

BRENDA2.7.11.16. 2681.
SignaLinkP43250.

Gene expression databases

ArrayExpressP43250.
BgeeP43250.
CleanExHS_GRK6.
GenevestigatorP43250.

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

EvolutionaryTraceP43250.
GeneWikiGRK6.
GenomeRNAi2870.
NextBio11323.
PROP43250.
SOURCESearch...

Entry information

Entry nameGRK6_HUMAN
AccessionPrimary (citable) accession number: P43250
Secondary accession number(s): O60541, Q13652
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1995
Last sequence update: January 23, 2002
Last modified: April 16, 2014
This is version 149 of the entry and version 2 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

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

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 5

Human chromosome 5: entries, gene names and cross-references to MIM