P50750 · CDK9_HUMAN
- ProteinCyclin-dependent kinase 9
- GeneCDK9
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids372 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849, PubMed:28426094, PubMed:30134174).
This complex is inactive when in the 7SK snRNP complex form (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849, PubMed:28426094).
Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR and the negative elongation factors DSIF and NELFE (PubMed:10912001, PubMed:11112772, PubMed:12037670, PubMed:20081228, PubMed:20980437, PubMed:21127351, PubMed:9857195).
Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling) (PubMed:17956865, PubMed:18362169).
Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis (PubMed:10393184, PubMed:11112772).
P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export (PubMed:15564463, PubMed:19575011, PubMed:19844166).
Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing (PubMed:15564463, PubMed:19575011, PubMed:19844166).
The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro (PubMed:21127351).
Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single-stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage (PubMed:20493174).
In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6 (PubMed:20493174).
Promotes cardiac myocyte enlargement (PubMed:20081228).
RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription (PubMed:21127351).
AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect (PubMed:10912001, PubMed:11112772, PubMed:9857195).
The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation (PubMed:12037670).
Catalyzes phosphorylation of KAT5, promoting KAT5 recruitment to chromatin and histone acetyltransferase activity (PubMed:29335245).
Miscellaneous
As a retroviruses target during the hijack of host transcription (e.g. HIV), CDK9 inhibitors might become specific antiretroviral agents (PubMed:18423896).
May be a target for cardiac hypertrophy future treatments (PubMed:18423896, PubMed:19757441).
May also be a target in anti-inflammatory therapy in innate immunity and systemic inflammation (PubMed:18728388).
Catalytic activity
- ATP + L-seryl-[protein] = ADP + H+ + O-phospho-L-seryl-[protein]This reaction proceeds in the forward direction.
Activity regulation
Features
Showing features for binding site, active site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameCyclin-dependent kinase 9
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP50750
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 44 | Impaired kinase and transcriptional elongation activities, but normal cyclin T1 and HEXIM1 binding. | ||||
Sequence: K → R | ||||||
Mutagenesis | 48 | Mimics acetylation; leading to impaired protein kinase activity. | ||||
Sequence: K → Q | ||||||
Mutagenesis | 48 | Decreased acetylation; leading to enhanced protein kinase activity. | ||||
Sequence: K → R | ||||||
Natural variant | VAR_041982 | 59 | in dbSNP:rs55640715 | |||
Sequence: F → L | ||||||
Mutagenesis | 167 | Abrogates kinase activity. | ||||
Sequence: D → N | ||||||
Mutagenesis | 175 | Constitutive kinase activity. | ||||
Sequence: S → A | ||||||
Mutagenesis | 175 | Mimics phosphorylation, constitutive loss of kinase activity. | ||||
Sequence: S → D | ||||||
Mutagenesis | 186 | Abrogates autophosphorylation; no effect on kinase activity, but impaired CTD phosphorylation. | ||||
Sequence: T → A | ||||||
Mutagenesis | 186 | Mimics autophosphorylation; constitutive kinase activity, independently of calcium signaling. | ||||
Sequence: T → D | ||||||
Natural variant | VAR_082140 | 225 | found in patients with global developmental delay and epilepsy with history of choanal atresia; uncertain significance; dbSNP:rs767418586 | |||
Sequence: R → C | ||||||
Natural variant | VAR_013456 | 231 | ||||
Sequence: G → A | ||||||
Mutagenesis | 347-357 | Loss of autophosphorylation and impaired interaction with HIVTAT. | ||||
Sequence: SQITQQSTNQS → AQIAQQAANQA | ||||||
Mutagenesis | 347-357 | Mimics autophosphorylation and promotes interaction with HIVTAT. | ||||
Sequence: SQITQQSTNQS → EQIEQQEENQE |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 341 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000085800 | 1-372 | UniProt | Cyclin-dependent kinase 9 | |||
Sequence: MAKQYDSVECPFCDEVSKYEKLAKIGQGTFGEVFKARHRKTGQKVALKKVLMENEKEGFPITALREIKILQLLKHENVVNLIEICRTKASPYNRCKGSIYLVFDFCEHDLAGLLSNVLVKFTLSEIKRVMQMLLNGLYYIHRNKILHRDMKAANVLITRDGVLKLADFGLARAFSLAKNSQPNRYTNRVVTLWYRPPELLLGERDYGPPIDLWGAGCIMAEMWTRSPIMQGNTEQHQLALISQLCGSITPEVWPNVDNYELYEKLELVKGQKRKVKDRLKAYVRDPYALDLIDKLLVLDPAQRIDSDDALNHDFFWSDPMPSDLKGMLSTHLTSMFEYLAPPRRKGSQITQQSTNQSRNPATTNQTEFERVF | |||||||
Modified residue | 35 | UniProt | In isoform P50750-2; Phosphoserine | ||||
Sequence: K | |||||||
Modified residue | 44 | UniProt | N6-acetyllysine; by EP300/CBP, PCAF/KAT2B and GCN5/KAT2A | ||||
Sequence: K | |||||||
Modified residue | 48 | UniProt | N6-acetyllysine; by PCAF/KAT2B and GCN5/KAT2A | ||||
Sequence: K | |||||||
Modified residue | 54 | UniProt | In isoform P50750-2; Phosphothreonine | ||||
Sequence: N | |||||||
Modified residue | 175 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 185 | PRIDE | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue | 186 | UniProt | Phosphothreonine; by CaMK1D | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 186 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue | 347 | UniProt | Phosphoserine; by CDK9 and PKA | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 347 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 350 | UniProt | Phosphothreonine; by CDK9 | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 350 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue | 353 | UniProt | Phosphoserine; by CDK9 | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 353 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 354 | UniProt | Phosphothreonine; by CDK9 | ||||
Sequence: T | |||||||
Modified residue | 357 | UniProt | Phosphoserine; by CDK9 | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 357 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 362 | UniProt | Phosphothreonine; by CDK9 | ||||
Sequence: T | |||||||
Modified residue | 363 | UniProt | Phosphothreonine; by CDK9 | ||||
Sequence: T |
Post-translational modification
The acetylated form associates with PML bodies in the nuclear matrix and with the transcriptionally silent HIV-1 genome; deacetylated upon transcription stimulation (PubMed:17452463, PubMed:18250157).
Deacetylated by SIRT7, promoting the kinase activity and subsequent 'Ser-2' phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (PubMed:28426094).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Induction
Gene expression databases
Organism-specific databases
Interaction
Subunit
Interacts with BRD4; to target chromatin binding (PubMed:16109376, PubMed:16109377, PubMed:18483222).
Interacts with JMJD6 (PubMed:24360279).
Interacts with activated nuclear STAT3 and RELA/p65 (PubMed:17956865, PubMed:18362169).
Binds to AR and MYOD1 (PubMed:12037670, PubMed:20980437).
Forms a complex composed of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates hypertrophy in cardiomyocytes (PubMed:20081228).
The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (By similarity).
Interacts with HSF1 (PubMed:27189267).
Interacts with TBX21 (By similarity).
Isoform 3: binds to KU70/XRCC6 (PubMed:20535204).
Interacts with WDR43 (By similarity).
Interacts with ZMYND8; the association appears to occur between homodimeric ZMYND8 and the activated form of the P-TEFb complex (PubMed:30134174).
Binary interactions
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 19-315 | Protein kinase | ||||
Sequence: YEKLAKIGQGTFGEVFKARHRKTGQKVALKKVLMENEKEGFPITALREIKILQLLKHENVVNLIEICRTKASPYNRCKGSIYLVFDFCEHDLAGLLSNVLVKFTLSEIKRVMQMLLNGLYYIHRNKILHRDMKAANVLITRDGVLKLADFGLARAFSLAKNSQPNRYTNRVVTLWYRPPELLLGERDYGPPIDLWGAGCIMAEMWTRSPIMQGNTEQHQLALISQLCGSITPEVWPNVDNYELYEKLELVKGQKRKVKDRLKAYVRDPYALDLIDKLLVLDPAQRIDSDDALNHDFF | ||||||
Region | 166-191 | T-loop | ||||
Sequence: ADFGLARAFSLAKNSQPNRYTNRVVT | ||||||
Region | 343-372 | Disordered | ||||
Sequence: RRKGSQITQQSTNQSRNPATTNQTEFERVF | ||||||
Compositional bias | 345-372 | Polar residues | ||||
Sequence: KGSQITQQSTNQSRNPATTNQTEFERVF |
Sequence similarities
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
P50750-1
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.
- Name1
- Length372
- Mass (Da)42,778
- Last updated2005-06-21 v3
- Checksum69E851CC6F7A0388
P50750-2
- Name2
- Differences from canonical
- 1-1: M → MQRDAPPRAPAPAPRLPAPPIGAAASSGGGGGGGSGGGGGGASAAPAPPGLSGTTSPRGPGGGRRAEEAGSAPRGRKWPWRRKWRGRGGAWSAAAAGPGAGAAAAATGGGGGALEAAM
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
X6RE90 | X6RE90_HUMAN | CDK9 | 194 |
Features
Showing features for alternative sequence, sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_016288 | 1 | in isoform 2 | |||
Sequence: M → MQRDAPPRAPAPAPRLPAPPIGAAASSGGGGGGGSGGGGGGASAAPAPPGLSGTTSPRGPGGGRRAEEAGSAPRGRKWPWRRKWRGRGGAWSAAAAGPGAGAAAAATGGGGGALEAAM | ||||||
Sequence conflict | 163 | in Ref. 4; AAV38706 | ||||
Sequence: L → P | ||||||
Compositional bias | 345-372 | Polar residues | ||||
Sequence: KGSQITQQSTNQSRNPATTNQTEFERVF |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
L25676 EMBL· GenBank· DDBJ | AAA35668.1 EMBL· GenBank· DDBJ | mRNA | ||
X80230 EMBL· GenBank· DDBJ | CAA56516.1 EMBL· GenBank· DDBJ | mRNA | ||
AF255306 EMBL· GenBank· DDBJ | AAF72183.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BT019903 EMBL· GenBank· DDBJ | AAV38706.1 EMBL· GenBank· DDBJ | mRNA | ||
AF517840 EMBL· GenBank· DDBJ | AAM54039.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AL162586 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC001968 EMBL· GenBank· DDBJ | AAH01968.1 EMBL· GenBank· DDBJ | mRNA |