Cyclin-dependent kinase 8

UniProt P49336 Organism Homo sapiens Gene CDK8 EC 2.7.11.22, 2.7.11.23

Also known as: CDK8

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 pre-initiation 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. Selectively regulates the interferon response by phosphorylating the transcription factor STAT1 transactivation domain (By similarity).

Classification

Family (Pfam): PF00069 Pkinase
InterPro: CDK, Kinase-like_dom_sf, Prot_kinase_dom, Protein_kinase_ATP_BS, Ser/Thr_kinase_AS
Functional cluster: RNase H & Viral Replication Proteins

Experimental structures · PDB · 36

3RGF X-ray 2.20A
4CRL X-ray 2.40A
4F6S X-ray 2.60A
4F6U X-ray 2.10A
4F6W X-ray 2.39A
4F70 X-ray 3.00A
4F7J X-ray 2.60A
4F7L X-ray 2.90A
4F7N X-ray 2.65A
4F7S X-ray 2.20A
4G6L X-ray 2.70A
5BNJ X-ray 2.64A
… and 24 more

A predicted model is available from AlphaFold.

Gene Ontology · 13

Disease associations

intellectual developmental disorder with hypotonia and behavioral abnormalities MONDO:0032897

Drugs targeting this protein · 4

PHA-793887 inhibitor
RONICICLIB inhibitor
AT-7519 inhibitor
AZD-5438 inhibitor

Related proteins · sequence + function similarity

Cyclin-dependent kinase 8 1.00
Cyclin-dependent kinase 8 1.00
Cyclin-dependent kinase 8 1.00
Cyclin-dependent kinase 19 0.98
Cyclin-dependent kinase 19 0.98
Cyclin-dependent kinase 8 0.90
Cyclin-dependent kinase 8 0.90
Cyclin-dependent kinase 8 0.87
MAP kinase-activated protein kinase 2 0.74
Casein kinase II subunit alpha 0.73
Casein kinase II subunit alpha 0.73
MAP kinase-activated protein kinase 2 0.73

Co-cited proteins · studied together in the literature

Cyclin-C 5 shared papers
Mastermind-like protein 1 1 shared papers
Mediator of RNA polymerase II transcription subunit 6 6 shared papers
Mediator of RNA polymerase II transcription subunit 21 4 shared papers
Mediator of RNA polymerase II transcription subunit 10 4 shared papers
Mediator of RNA polymerase II transcription subunit 23 4 shared papers
Mediator of RNA polymerase II transcription subunit 14 4 shared papers
Mediator of RNA polymerase II transcription subunit 1 4 shared papers
Mediator of RNA polymerase II transcription subunit 12 3 shared papers
Cyclin-H 1 shared papers
Mediator of RNA polymerase II transcription subunit 31 3 shared papers
Mediator of RNA polymerase II transcription subunit 24 3 shared papers

Literature · 14 cited papers

De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder. Am. J. Hum. Genet. · 2019
The structure of CDK8/CycC implicates specificity in the CDK/cyclin family and reveals interaction with a deep pocket binder. J. Mol. Biol. · 2011
Large-scale proteomics analysis of the human kinome. Mol. Cell. Proteomics · 2009
Patterns of somatic mutation in human cancer genomes. Nature · 2007
Mediator modulates Gli3-dependent Sonic hedgehog signaling. Mol. Cell. Biol. · 2006
MED1/TRAP220 exists predominantly in a TRAP/Mediator subpopulation enriched in RNA polymerase II and is required for ER-mediated transcription. Mol. Cell · 2005
Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol. Cell · 2004
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology. Mol. Cell · 2004
The DNA sequence and analysis of human chromosome 13. Nature · 2004
TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature · 2000
A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation. Mol. Cell · 1999
… and 2 more in the literature graph

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