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Q5EAB2

- CDK9_BOVIN

UniProt

Q5EAB2 - CDK9_BOVIN

Protein

Cyclin-dependent kinase 9

Gene

CDK9

Organism
Bos taurus (Bovine)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at transcript leveli
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    • History
      Entry version 95 (01 Oct 2014)
      Sequence version 1 (15 Mar 2005)
      Previous versions | rss
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    Functioni

    Protein kinase involved in the regulation of transcription. 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. This complex is inactive when in the 7SK snRNP complex form. Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR, and the negative elongation factors DSIF and NELF. 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). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis. P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export. 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. 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. 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. In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement. RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription. AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect. The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation By similarity.By similarity

    Catalytic activityi

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

    Enzyme regulationi

    Activation by Thr-186 phosphorylation is calcium Ca2+ signaling pathway-dependent; actively inactivated by dephosphorylation mediated by PPP1CA, PPM1A and PPM1B. Reversibly repressed by acetylation at Lys-44 and Lys-48 By similarity.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei48 – 481ATPPROSITE-ProRule annotation
    Active sitei149 – 1491Proton acceptorPROSITE-ProRule annotation
    Binding sitei167 – 1671ATPPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi25 – 339ATPPROSITE-ProRule annotation
    Nucleotide bindingi104 – 1063ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. chromatin binding Source: Ensembl
    3. cyclin-dependent protein serine/threonine kinase activity Source: UniProtKB-EC
    4. RNA polymerase II carboxy-terminal domain kinase activity Source: UniProtKB-EC
    5. snRNA binding Source: Ensembl
    6. transcription regulatory region DNA binding Source: Ensembl

    GO - Biological processi

    1. cellular response to cytokine stimulus Source: Ensembl
    2. DNA repair Source: UniProtKB-KW
    3. negative regulation of cell cycle arrest Source: Ensembl
    4. regulation of DNA repair Source: Ensembl
    5. regulation of histone modification Source: Ensembl
    6. regulation of transcription, DNA-templated Source: UniProtKB-KW
    7. replication fork arrest Source: Ensembl
    8. transcription, DNA-templated Source: UniProtKB-KW

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    DNA damage, DNA repair, Transcription, Transcription regulation

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    ReactomeiREACT_205499. RNA Polymerase II Pre-transcription Events.
    REACT_218933. RNA Polymerase II Transcription Elongation.
    REACT_224116. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Cyclin-dependent kinase 9 (EC:2.7.11.22, EC:2.7.11.23)
    Alternative name(s):
    Cell division protein kinase 9
    Gene namesi
    Name:CDK9
    OrganismiBos taurus (Bovine)
    Taxonomic identifieri9913 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
    ProteomesiUP000009136: Chromosome 11

    Subcellular locationi

    Nucleus By similarity. Cytoplasm By similarity. NucleusPML body By similarity
    Note: Accumulates on chromatin in response to replication stress. Complexed with CCNT1 in nuclear speckles, but uncomplexed form in the cytoplasm. The translocation from nucleus to cytoplasm is XPO1/CRM1-dependent. Associates with PML body when acetylated By similarity.By similarity

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB-SubCell
    2. PML body Source: UniProtKB-SubCell
    3. positive transcription elongation factor complex b Source: UniProtKB

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 372372Cyclin-dependent kinase 9PRO_0000085799Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei29 – 291PhosphothreonineBy similarity
    Modified residuei44 – 441N6-acetyllysine; by P300/CBP, PCAF/KAT2B and GCN5/KAT2ABy similarity
    Modified residuei48 – 481N6-acetyllysine; by PCAF/KAT2B and GCN5/KAT2ABy similarity
    Modified residuei175 – 1751PhosphoserineBy similarity
    Modified residuei186 – 1861Phosphothreonine; by CaMK1DBy similarity
    Modified residuei347 – 3471Phosphoserine; by CDK9 and PKABy similarity
    Modified residuei350 – 3501Phosphothreonine; by CDK9By similarity
    Modified residuei353 – 3531Phosphoserine; by CDK9By similarity
    Modified residuei354 – 3541Phosphothreonine; by CDK9By similarity
    Modified residuei357 – 3571Phosphoserine; by CDK9By similarity
    Modified residuei362 – 3621Phosphothreonine; by CDK9By similarity
    Modified residuei363 – 3631Phosphothreonine; by CDK9By similarity

    Post-translational modificationi

    Autophosphorylation at Thr-186, Ser-347, Thr-350, Ser-353, Thr-354 and Ser-357 triggers kinase activity by promoting cyclin and substrate binding upon conformational changes. Thr-186 phosphorylation requires the calcium Ca2+ signaling pathway, including CaMK1D and calmodulin. This inhibition is relieved by Thr-29 dephosphorylation. Phosphorylation at Ser-175 inhibits kinase activity. Can be phosphorylated on either Thr-362 or Thr-363 but not on both simultaneously By similarity.By similarity
    Dephosphorylation of Thr-186 by PPM1A and PPM1B blocks CDK9 activity and may lead to CDK9 proteasomal degradation. However, PPP1CA-mediated Thr-186 dephosphorylation is required to release P-TEFb from its inactive P-TEFb/7SK snRNP complex. Dephosphorylation of C-terminus Thr and Ser residues by protein phosphatase-1 (PP1) triggers CDK9 activity By similarity.By similarity
    N6-acetylation of Lys-44 by CBP/p300 promotes kinase activity, whereas acetylation of both Lys-44 and Lys-48 mediated by PCAF/KAT2B and GCN5/KAT2A reduces kinase activity. The acetylated form associates with PML bodies in the nuclear matrix; deacetylated upon transcription stimulation By similarity.By similarity
    Polyubiquitinated and thus activated by UBR5. This ubiquitination is promoted by TFIIS/TCEA1 and favors 'Ser-2' phosphorylation of RPB1/POLR2A CTD By similarity.By similarity

    Keywords - PTMi

    Acetylation, Phosphoprotein, Ubl conjugation

    Proteomic databases

    PRIDEiQ5EAB2.

    Interactioni

    Subunit structurei

    Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3). Associates with CCNT1/cyclin-T1, CCNT2/cyclin-T2 (isoform A and isoform B) or CCNK/cyclin-K to form active P-TEFb. P-TEFb forms a complex with AFF4/AF5Q31 and is part of the super elongation complex (SEC). Component of a complex which is composed of at least 5 members: HTATSF1/Tat-SF1, P-TEFb complex, RNA pol II, SUPT5H, and NCL/nucleolin. Associates with UBR5 and forms a transcription regulatory complex composed of CDK9, RNAP II, UBR5 and TFIIS/TCEA1 that can stimulate target gene transcription (e.g. gamma fibrinogen/FGG) by recruiting their promoters. Component of the 7SK snRNP inactive complex which is composed of at least 8 members: P-TEFb (composed of CDK9 and CCNT1/cyclin-T1), HEXIM1, HEXIM2, LARP7, BCDIN3, SART3 proteins and 7SK and U6 snRNAs. This inactive 7SK snRNP complex can also interact with NCOR1 and HDAC3, probably to regulate CDK9 acetylation. Release of P-TEFb from P-TEFb/7SK snRNP complex requires both PP2B to transduce calcium Ca2+ signaling in response to stimuli (e.g. UV or hexamethylene bisacetamide (HMBA)), and PPP1CA to dephosphorylate Thr-186. This released P-TEFb remains inactive in the pre-initiation complex with BRD4 until new Thr-186 phosphorylation occurs after the synthesis of a short RNA. Interacts with BRD4, probably to target chromatin binding. Interacts with activated nuclear STAT3 and RELA/p65. Binds to AR and MYOD1. Forms a complex composed of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates hypertrophy in cardiomyocytes. 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.By similarity

    Structurei

    3D structure databases

    ProteinModelPortaliQ5EAB2.
    SMRiQ5EAB2. Positions 7-326.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini19 – 315297Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni166 – 19126T-loopBy similarityAdd
    BLAST

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00740000114964.
    HOGENOMiHOG000233024.
    HOVERGENiHBG014652.
    InParanoidiQ5EAB2.
    KOiK02211.
    OMAiMELPKGQ.
    OrthoDBiEOG76DTSM.
    TreeFamiTF101039.

    Family and domain databases

    InterProiIPR011009. 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]
    PfamiPF00069. Pkinase. 1 hit.
    [Graphical view]
    SMARTiSM00220. S_TKc. 1 hit.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 1 hit.
    PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q5EAB2-1 [UniParc]FASTAAdd to Basket

    « Hide

    MAKQYDSVEC PFCDEVTKYE KLAKIGQGTF GEVFKAKHRK TGQKVALKKV    50
    LMENEKEGFP ITALREIKIL QLLKHENVVN LIEICRTKAS PYNRCKGSIY 100
    LVFDFCEHDL AGLLSNVLVK FTLSEIKRVM QMLLNGLYYI HRNKILHRDM 150
    KAANVLITRD GVLKLADFGL ARAFSLAKNS QPNRYTNRVV TLWYRPPELL 200
    LGERDYGPPI DLWGAGCIMA EMWTRSPIMQ GNTEQHQLAL ISQLCGSITP 250
    EVWPNVDKYE LFEKVELVKG QKRKVKDRLK AYVRDPYALD LIDKLLVLDP 300
    AQRIDSDDAL NHDFFWSDPM PSDLKGMLST HLTSMFEYLA PPRRKGSQIT 350
    QQSTNQSRNP ATTNQTEFER VF 372
    Length:372
    Mass (Da):42,748
    Last modified:March 15, 2005 - v1
    Checksum:i50A26ECAC9A36CAD
    GO

    Sequence cautioni

    The sequence AAX46729.1 differs from that shown. Reason: Frameshift at position 231.

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    BT020657 mRNA. Translation: AAX08674.1.
    BT021882 mRNA. Translation: AAX46729.1. Frameshift.
    BC118194 mRNA. Translation: AAI18195.1.
    RefSeqiNP_001014935.2. NM_001014935.2.
    UniGeneiBt.1465.

    Genome annotation databases

    EnsembliENSBTAT00000006162; ENSBTAP00000006162; ENSBTAG00000004695.
    GeneIDi520580.
    KEGGibta:520580.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    BT020657 mRNA. Translation: AAX08674.1 .
    BT021882 mRNA. Translation: AAX46729.1 . Frameshift.
    BC118194 mRNA. Translation: AAI18195.1 .
    RefSeqi NP_001014935.2. NM_001014935.2.
    UniGenei Bt.1465.

    3D structure databases

    ProteinModelPortali Q5EAB2.
    SMRi Q5EAB2. Positions 7-326.
    ModBasei Search...
    MobiDBi Search...

    Proteomic databases

    PRIDEi Q5EAB2.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSBTAT00000006162 ; ENSBTAP00000006162 ; ENSBTAG00000004695 .
    GeneIDi 520580.
    KEGGi bta:520580.

    Organism-specific databases

    CTDi 1025.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00740000114964.
    HOGENOMi HOG000233024.
    HOVERGENi HBG014652.
    InParanoidi Q5EAB2.
    KOi K02211.
    OMAi MELPKGQ.
    OrthoDBi EOG76DTSM.
    TreeFami TF101039.

    Enzyme and pathway databases

    Reactomei REACT_205499. RNA Polymerase II Pre-transcription Events.
    REACT_218933. RNA Polymerase II Transcription Elongation.
    REACT_224116. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.

    Miscellaneous databases

    NextBioi 20873133.

    Family and domain databases

    InterProi IPR011009. 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 ]
    Pfami PF00069. Pkinase. 1 hit.
    [Graphical view ]
    SMARTi SM00220. S_TKc. 1 hit.
    [Graphical view ]
    SUPFAMi SSF56112. SSF56112. 1 hit.
    PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
    PS50011. PROTEIN_KINASE_DOM. 1 hit.
    PS00108. PROTEIN_KINASE_ST. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    2. NIH - Mammalian Gene Collection (MGC) project
      Submitted (JUN-2006) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Strain: Hereford.
      Tissue: Thalamus.

    Entry informationi

    Entry nameiCDK9_BOVIN
    AccessioniPrimary (citable) accession number: Q5EAB2
    Secondary accession number(s): Q148K6, Q58CR5
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 22, 2005
    Last sequence update: March 15, 2005
    Last modified: October 1, 2014
    This is version 95 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3