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P49336 (CDK8_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 132. 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:
Cyclin-dependent kinase 8

EC=2.7.11.22
EC=2.7.11.23
Alternative name(s):
Cell division protein kinase 8
Mediator complex subunit CDK8
Mediator of RNA polymerase II transcription subunit CDK8
Protein kinase K35
Gene names
Name:CDK8
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length464 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation. Ref.8 Ref.9

Catalytic activity

ATP + a protein = ADP + a phosphoprotein. Ref.8

ATP + [DNA-directed RNA polymerase] = ADP + [DNA-directed RNA polymerase] phosphate. Ref.8

Cofactor

Magnesium By similarity.

Subunit structure

Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. The cylin/CDK pair formed by CCNC/CDK8 also associates with the large subunit of RNA polymerase II. Interacts with CTNNB1, GLI3 and MAML1. Ref.5 Ref.6 Ref.9 Ref.10 Ref.11 Ref.12

Subcellular location

Nucleus Probable.

Sequence similarities

Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processTranscription
Transcription regulation
   Cellular componentNucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   LigandATP-binding
Nucleotide-binding
   Molecular functionActivator
Kinase
Repressor
Serine/threonine-protein kinase
Transferase
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processNotch signaling pathway

Traceable author statement. Source: Reactome

gene expression

Traceable author statement. Source: Reactome

positive regulation of transcription from RNA polymerase II promoter

Traceable author statement. Source: Reactome

transcription initiation from RNA polymerase II promoter

Traceable author statement. Source: Reactome

transcription, DNA-templated

Traceable author statement. Source: Reactome

transforming growth factor beta receptor signaling pathway

Traceable author statement. Source: Reactome

   Cellular_componentmediator complex

Inferred from direct assay PubMed 14638676. Source: MGI

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay PubMed 16109376. Source: MGI

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

RNA polymerase II carboxy-terminal domain kinase activity

Inferred from electronic annotation. Source: UniProtKB-EC

cyclin-dependent protein serine/threonine kinase activity

Inferred from electronic annotation. Source: UniProtKB-EC

protein kinase activity

Traceable author statement Ref.1. Source: ProtInc

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

CCNCP248636EBI-394377,EBI-395261

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P49336-1)

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 2 (identifier: P49336-2)

The sequence of this isoform differs from the canonical sequence as follows:
     370-370: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 464464Cyclin-dependent kinase 8
PRO_0000085797

Regions

Domain21 – 335315Protein kinase
Nucleotide binding27 – 359ATP By similarity
Region1 – 1515Interaction with CCNC
Compositional bias373 – 3775Poly-Gln

Sites

Active site1511Proton acceptor By similarity
Binding site521ATP By similarity

Natural variations

Alternative sequence3701Missing in isoform 2.
VSP_029970
Natural variant1891D → N in a lung neuroendocrine carcinoma sample; somatic mutation. Ref.15
VAR_041980
Natural variant4241R → C in a colorectal adenocarcinoma sample; somatic mutation. Ref.15
VAR_041981

Experimental info

Mutagenesis1731D → A: Abrogates kinase activity and TFIIH-dependent transcriptional repression. Ref.8

Secondary structure

......................................................... 464
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified February 1, 1996. Version 1.
Checksum: 00CBAB6CE354605F

FASTA46453,284
        10         20         30         40         50         60 
MDYDFKVKLS SERERVEDLF EYEGCKVGRG TYGHVYKAKR KDGKDDKDYA LKQIEGTGIS 

        70         80         90        100        110        120 
MSACREIALL RELKHPNVIS LQKVFLSHAD RKVWLLFDYA EHDLWHIIKF HRASKANKKP 

       130        140        150        160        170        180 
VQLPRGMVKS LLYQILDGIH YLHANWVLHR DLKPANILVM GEGPERGRVK IADMGFARLF 

       190        200        210        220        230        240 
NSPLKPLADL DPVVVTFWYR APELLLGARH YTKAIDIWAI GCIFAELLTS EPIFHCRQED 

       250        260        270        280        290        300 
IKTSNPYHHD QLDRIFNVMG FPADKDWEDI KKMPEHSTLM KDFRRNTYTN CSLIKYMEKH 

       310        320        330        340        350        360 
KVKPDSKAFH LLQKLLTMDP IKRITSEQAM QDPYFLEDPL PTSDVFAGCQ IPYPKREFLT 

       370        380        390        400        410        420 
EEEPDDKGDK KNQQQQQGNN HTNGTGHPGN QDSSHTQGPP LKKVRVVPPT TTSGGLIMTS 

       430        440        450        460 
DYQRSNPHAA YPNPGPSTSQ PQSSMGYSAT SQQPPQYSHQ THRY 

« Hide

Isoform 2 [UniParc].

Checksum: 8C74EEBD24CBA5DB
Show »

FASTA46353,156

References

« Hide 'large scale' references
[1]"Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C."
Tassan J.-P., Jaquenoud M., Leopold P., Schultz S.J., Nigg E.A.
Proc. Natl. Acad. Sci. U.S.A. 92:8871-8875(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Testis.
[2]"The DNA sequence and analysis of human chromosome 13."
Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T. expand/collapse author list , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L., Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.
Nature 428:522-528(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
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] (ISOFORMS 1 AND 2).
[5]"NAT, a human complex containing Srb polypeptides that functions as a negative regulator of activated transcription."
Sun X., Zhang Y., Cho H., Rickert P., Lees E., Lane W.S., Reinberg D.
Mol. Cell 2:213-222(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN THE MEDIATOR COMPLEX.
[6]"A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation."
Gu W., Malik S., Ito M., Yuan C.-X., Fondell J.D., Zhang X., Martinez E., Qin J., Roeder R.G.
Mol. Cell 3:97-108(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN THE SMCC COMPLEX.
[7]Erratum
Gu W., Malik S., Ito M., Yuan C.-X., Fondell J.D., Zhang X., Martinez E., Qin J., Roeder R.G.
Mol. Cell 3:541-541(1999)
[8]"TFIIH is negatively regulated by cdk8-containing mediator complexes."
Akoulitchev S., Chuikov S., Reinberg D.
Nature 407:102-106(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-173.
[9]"Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover."
Fryer C.J., White J.B., Jones K.A.
Mol. Cell 16:509-520(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH MAML1.
[10]"A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology."
Sato S., Tomomori-Sato C., Parmely T.J., Florens L., Zybailov B., Swanson S.K., Banks C.A.S., Jin J., Cai Y., Washburn M.P., Conaway J.W., Conaway R.C.
Mol. Cell 14:685-691(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN THE MEDIATOR COMPLEX.
[11]"MED1/TRAP220 exists predominantly in a TRAP/Mediator subpopulation enriched in RNA polymerase II and is required for ER-mediated transcription."
Zhang X., Krutchinsky A., Fukuda A., Chen W., Yamamura S., Chait B.T., Roeder R.G.
Mol. Cell 19:89-100(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN THE MEDIATOR COMPLEX, ASSOCIATION OF THE MEDIATOR COMPLEX WITH RNA POLYMERASE II.
[12]"Mediator modulates Gli3-dependent Sonic hedgehog signaling."
Zhou H., Kim S., Ishii S., Boyer T.G.
Mol. Cell. Biol. 26:8667-8682(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CTNNB1; GLI3; MED1; MED6; MED12 AND MED23.
[13]"Large-scale proteomics analysis of the human kinome."
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H.
Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[14]"The structure of CDK8/CycC implicates specificity in the CDK/cyclin family and reveals interaction with a deep pocket binder."
Schneider E.V., Bottcher J., Blaesse M., Neumann L., Huber R., Maskos K.
J. Mol. Biol. 412:251-266(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-403 IN COMPLEX WITH CCNC AND INHIBITOR.
[15]"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] ASN-189 AND CYS-424.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X85753 mRNA. Translation: CAA59754.1.
AL590108, AL159159 Genomic DNA. Translation: CAH72300.1.
AL159159, AL590108 Genomic DNA. Translation: CAI16960.1.
CH471075 Genomic DNA. Translation: EAX08386.1.
CH471075 Genomic DNA. Translation: EAX08387.1.
BC069634 mRNA. Translation: AAH69634.1.
BC104492 mRNA. Translation: AAI04493.1.
BC105950 mRNA. Translation: AAI05951.1.
BC107601 mRNA. Translation: AAI07602.1.
PIRI37227.
RefSeqNP_001251.1. NM_001260.1.
XP_005266272.1. XM_005266215.1.
UniGeneHs.382306.
Hs.695166.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3RGFX-ray2.20A1-403[»]
4F6SX-ray2.60A1-403[»]
4F6UX-ray2.10A1-403[»]
4F6WX-ray2.39A1-403[»]
4F70X-ray3.00A1-403[»]
4F7JX-ray2.60A1-403[»]
4F7LX-ray2.90A1-403[»]
4F7NX-ray2.65A1-403[»]
4F7SX-ray2.20A1-403[»]
4G6LX-ray2.70A1-403[»]
ProteinModelPortalP49336.
SMRP49336. Positions 1-359.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid107458. 76 interactions.
DIPDIP-32595N.
IntActP49336. 39 interactions.
MINTMINT-3017285.
STRING9606.ENSP00000370938.

Chemistry

BindingDBP49336.
ChEMBLCHEMBL5719.
GuidetoPHARMACOLOGY1980.

PTM databases

PhosphoSiteP49336.

Polymorphism databases

DMDM1345718.

Proteomic databases

PaxDbP49336.
PRIDEP49336.

Protocols and materials databases

DNASU1024.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000381527; ENSP00000370938; ENSG00000132964. [P49336-1]
GeneID1024.
KEGGhsa:1024.
UCSCuc001uqr.1. human. [P49336-1]
uc001uqs.1. human. [P49336-2]

Organism-specific databases

CTD1024.
GeneCardsGC13P026828.
HGNCHGNC:1779. CDK8.
MIM603184. gene.
neXtProtNX_P49336.
PharmGKBPA26315.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000233024.
HOVERGENHBG014652.
InParanoidP49336.
KOK02208.
OMANVITLIR.
PhylomeDBP49336.
TreeFamTF101025.

Enzyme and pathway databases

BRENDA2.7.11.22. 2681.
ReactomeREACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_71. Gene Expression.
SignaLinkP49336.

Gene expression databases

ArrayExpressP49336.
BgeeP49336.
CleanExHS_CDK8.
GenevestigatorP49336.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSCDK8. human.
GeneWikiCyclin-dependent_kinase_8.
GenomeRNAi1024.
NextBio4301.
PROP49336.
SOURCESearch...

Entry information

Entry nameCDK8_HUMAN
AccessionPrimary (citable) accession number: P49336
Secondary accession number(s): Q5VUF3, Q6ISB5
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: February 1, 1996
Last modified: April 16, 2014
This is version 132 of the entry and version 1 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 13

Human chromosome 13: entries, gene names and cross-references to MIM