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Protein

Cyclin-dependent kinase 8

Gene

CDK8

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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.2 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.1 Publication
ATP + [DNA-directed RNA polymerase] = ADP + [DNA-directed RNA polymerase] phosphate.1 Publication

Cofactori

Mg2+By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei52ATPPROSITE-ProRule annotation1
Active sitei151Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi27 – 35ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionActivator, Kinase, Repressor, Serine/threonine-protein kinase, Transferase
Biological processTranscription, Transcription regulation
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.22 2681
ReactomeiR-HSA-1989781 PPARA activates gene expression
R-HSA-2122947 NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-212436 Generic Transcription Pathway
R-HSA-2173796 SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-2644606 Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862 Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-381340 Transcriptional regulation of white adipocyte differentiation
SignaLinkiP49336
SIGNORiP49336

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:CDK8
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 13

Organism-specific databases

EuPathDBiHostDB:ENSG00000132964.11
HGNCiHGNC:1779 CDK8
MIMi603184 gene
neXtProtiNX_P49336

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi173D → A: Abrogates kinase activity and TFIIH-dependent transcriptional repression. 1 Publication1

Organism-specific databases

DisGeNETi1024
OpenTargetsiENSG00000132964
PharmGKBiPA26315

Chemistry databases

ChEMBLiCHEMBL5719
DrugBankiDB03496 Flavopiridol
GuidetoPHARMACOLOGYi1980

Polymorphism and mutation databases

BioMutaiCDK8
DMDMi1345718

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000857971 – 464Cyclin-dependent kinase 8Add BLAST464

Proteomic databases

EPDiP49336
MaxQBiP49336
PaxDbiP49336
PeptideAtlasiP49336
PRIDEiP49336
ProteomicsDBi55991
55992 [P49336-2]

PTM databases

iPTMnetiP49336
PhosphoSitePlusiP49336

Expressioni

Gene expression databases

BgeeiENSG00000132964
CleanExiHS_CDK8
ExpressionAtlasiP49336 baseline and differential
GenevisibleiP49336 HS

Organism-specific databases

HPAiHPA044721

Interactioni

Subunit structurei

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 MAML1.7 Publications

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi107458, 110 interactors
ComplexPortaliCPX-1969 Cyclin C-CDK8 complex
CPX-3232 CKM complex variant 1
CORUMiP49336
DIPiDIP-32595N
IntActiP49336, 177 interactors
MINTiP49336
STRINGi9606.ENSP00000370938

Chemistry databases

BindingDBiP49336

Structurei

Secondary structure

1464
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi3 – 12Combined sources10
Helixi16 – 19Combined sources4
Beta strandi26 – 30Combined sources5
Beta strandi33 – 44Combined sources12
Beta strandi49 – 58Combined sources10
Helixi61 – 72Combined sources12
Beta strandi83 – 87Combined sources5
Turni88 – 91Combined sources4
Beta strandi92 – 98Combined sources7
Beta strandi101 – 103Combined sources3
Helixi104 – 115Combined sources12
Turni116 – 118Combined sources3
Helixi125 – 144Combined sources20
Helixi154 – 156Combined sources3
Beta strandi157 – 159Combined sources3
Turni164 – 167Combined sources4
Beta strandi169 – 171Combined sources3
Helixi179 – 181Combined sources3
Beta strandi186 – 188Combined sources3
Helixi202 – 205Combined sources4
Helixi213 – 229Combined sources17
Helixi249 – 259Combined sources11
Turni264 – 266Combined sources3
Helixi268 – 272Combined sources5
Helixi276 – 282Combined sources7
Helixi285 – 288Combined sources4
Helixi293 – 299Combined sources7
Helixi307 – 315Combined sources9
Helixi320 – 322Combined sources3
Helixi326 – 330Combined sources5
Helixi333 – 335Combined sources3
Beta strandi337 – 339Combined sources3
Turni345 – 348Combined sources4

3D structure databases

ProteinModelPortaliP49336
SMRiP49336
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini21 – 335Protein kinasePROSITE-ProRule annotationAdd BLAST315

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 15Interaction with CCNCAdd BLAST15

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi373 – 377Poly-Gln5

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0666 Eukaryota
ENOG410XPPA LUCA
GeneTreeiENSGT00530000064012
HOGENOMiHOG000233024
HOVERGENiHBG014652
InParanoidiP49336
KOiK02208
OMAiKSIYMVF
OrthoDBiEOG091G0812
PhylomeDBiP49336
TreeFamiTF101025

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P49336-1) [UniParc]FASTAAdd to basket

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.

« Hide

        10         20         30         40         50
MDYDFKVKLS SERERVEDLF EYEGCKVGRG TYGHVYKAKR KDGKDDKDYA
60 70 80 90 100
LKQIEGTGIS MSACREIALL RELKHPNVIS LQKVFLSHAD RKVWLLFDYA
110 120 130 140 150
EHDLWHIIKF HRASKANKKP VQLPRGMVKS LLYQILDGIH YLHANWVLHR
160 170 180 190 200
DLKPANILVM GEGPERGRVK IADMGFARLF NSPLKPLADL DPVVVTFWYR
210 220 230 240 250
APELLLGARH YTKAIDIWAI GCIFAELLTS EPIFHCRQED IKTSNPYHHD
260 270 280 290 300
QLDRIFNVMG FPADKDWEDI KKMPEHSTLM KDFRRNTYTN CSLIKYMEKH
310 320 330 340 350
KVKPDSKAFH LLQKLLTMDP IKRITSEQAM QDPYFLEDPL PTSDVFAGCQ
360 370 380 390 400
IPYPKREFLT EEEPDDKGDK KNQQQQQGNN HTNGTGHPGN QDSSHTQGPP
410 420 430 440 450
LKKVRVVPPT TTSGGLIMTS DYQRSNPHAA YPNPGPSTSQ PQSSMGYSAT
460
SQQPPQYSHQ THRY
Length:464
Mass (Da):53,284
Last modified:February 1, 1996 - v1
Checksum:i00CBAB6CE354605F
GO
Isoform 2 (identifier: P49336-2) [UniParc]FASTAAdd to basket

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

Show »
Length:463
Mass (Da):53,156
Checksum:i8C74EEBD24CBA5DB
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_041980189D → N in a lung neuroendocrine carcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_041981424R → C in a colorectal adenocarcinoma sample; somatic mutation. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_029970370Missing in isoform 2. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X85753 mRNA Translation: CAA59754.1
AL159159 Genomic DNA No translation available.
AL590108 Genomic DNA No translation available.
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
CCDSiCCDS9317.1 [P49336-1]
PIRiI37227
RefSeqiNP_001251.1, NM_001260.2 [P49336-1]
NP_001305297.1, NM_001318368.1 [P49336-2]
UniGeneiHs.382306
Hs.695166

Genome annotation databases

EnsembliENST00000381527; ENSP00000370938; ENSG00000132964 [P49336-1]
GeneIDi1024
KEGGihsa:1024
UCSCiuc001uqr.2 human [P49336-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiCDK8_HUMAN
AccessioniPrimary (citable) accession number: P49336
Secondary accession number(s): Q5VUF3, Q6ISB5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
Last sequence update: February 1, 1996
Last modified: July 18, 2018
This is version 173 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 13
    Human chromosome 13: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

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