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Q02399

- CDK5_BOVIN

UniProt

Q02399 - CDK5_BOVIN

Protein

Cyclin-dependent-like kinase 5

Gene

CDK5

Organism
Bos taurus (Bovine)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 132 (01 Oct 2014)
      Sequence version 2 (13 Nov 2007)
      Previous versions | rss
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    Functioni

    Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. Interacts with D1 and D3-type G1 cyclins. Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in post-mitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Phosphorylates also exocytosis associated proteins such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. In the mature central nervous system (CNS), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis producing p25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precedes neuronal death by deregulating HDAC1. DNA damage triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Negative regulator of Wnt/beta-catenin signaling pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma-dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer in association with altered stability and subcellular distribution By similarity.By similarity

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.

    Enzyme regulationi

    Inhibited by 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine), 1-isopropyl-4-aminobenzyl-6-ether-linked benzimidazoles, resveratrol, AT-7519 and olomoucine. Activated by CDK5R1 (p35) and CDK5R2 (p39) during the development of the nervous system; degradation of CDK5R1 (p35) and CDK5R2 (p39) by proteasome result in down regulation of kinase activity, during this process, CDK5 phosphorylates p35 and induces its ubiquitination and subsequent degradation. Kinase activity is mainly determined by the amount of p35 available and subcellular location; reversible association to plasma membrane inhibits activity. Long-term inactivation as well as CDK5R1 (p25)-mediated hyperactivation of CDK5 triggers cell death. The pro-death activity of hyperactivated CDK5 is suppressed by membrane association of CDK5, via myristoylation of p35. Brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor (NGF), retinoic acid, laminin and neuregulin promote activity. Neurotoxicity enhances nuclear activity, thus leading to MEF2 phosphorylation and inhibition prior to apoptosis of cortical neurons. Repression by GSTP1 via p25/p35 translocation prevents neurodegeneration By similarity.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei33 – 331ATPPROSITE-ProRule annotation
    Active sitei126 – 1261Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi10 – 189ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. acetylcholine receptor activator activity Source: AgBase
    2. ATP binding Source: UniProtKB-KW
    3. cyclin-dependent protein serine/threonine kinase activity Source: UniProtKB
    4. ErbB-2 class receptor binding Source: AgBase
    5. ErbB-3 class receptor binding Source: UniProtKB
    6. histone kinase activity Source: UniProtKB
    7. kinase activity Source: AgBase
    8. protein serine/threonine kinase activity Source: AgBase
    9. tau-protein kinase activity Source: AgBase

    GO - Biological processi

    1. axonogenesis Source: AgBase
    2. behavioral response to cocaine Source: Ensembl
    3. calcium ion import Source: Ensembl
    4. cell cycle Source: UniProtKB-KW
    5. cell division Source: UniProtKB-KW
    6. cell-matrix adhesion Source: AgBase
    7. cell migration Source: AgBase
    8. central nervous system neuron development Source: Ensembl
    9. cerebellar cortex formation Source: Ensembl
    10. corpus callosum development Source: Ensembl
    11. dendrite morphogenesis Source: Ensembl
    12. embryo development Source: AgBase
    13. hippocampus development Source: Ensembl
    14. histone phosphorylation Source: GOC
    15. intracellular protein transport Source: Ensembl
    16. layer formation in cerebral cortex Source: Ensembl
    17. motor neuron axon guidance Source: Ensembl
    18. negative regulation of axon extension Source: Ensembl
    19. negative regulation of cell cycle Source: Ensembl
    20. negative regulation of protein export from nucleus Source: Ensembl
    21. negative regulation of protein ubiquitination Source: Ensembl
    22. negative regulation of synaptic plasticity Source: Ensembl
    23. negative regulation of transcription, DNA-templated Source: Ensembl
    24. neuron apoptotic process Source: Ensembl
    25. neuron differentiation Source: AgBase
    26. neuron migration Source: Ensembl
    27. neuron projection development Source: AgBase
    28. oligodendrocyte differentiation Source: Ensembl
    29. peptidyl-threonine phosphorylation Source: Ensembl
    30. positive regulation of calcium ion-dependent exocytosis Source: Ensembl
    31. positive regulation of neuron apoptotic process Source: UniProtKB
    32. positive regulation of protein binding Source: Ensembl
    33. positive regulation of protein kinase activity Source: Ensembl
    34. positive regulation of protein targeting to membrane Source: Ensembl
    35. positive regulation of receptor activity Source: GOC
    36. protein localization to synapse Source: Ensembl
    37. receptor catabolic process Source: Ensembl
    38. receptor clustering Source: Ensembl
    39. regulation of cell migration Source: AgBase
    40. regulation of dendritic spine morphogenesis Source: UniProtKB
    41. regulation of excitatory postsynaptic membrane potential Source: Ensembl
    42. regulation of synaptic plasticity Source: UniProtKB
    43. rhythmic process Source: UniProtKB-KW
    44. Schwann cell development Source: Ensembl
    45. sensory perception of pain Source: Ensembl
    46. serine phosphorylation of STAT3 protein Source: Ensembl
    47. skeletal muscle tissue development Source: Ensembl
    48. synapse assembly Source: Ensembl
    49. synaptic transmission, dopaminergic Source: Ensembl
    50. synaptic transmission, glutamatergic Source: Ensembl
    51. visual learning Source: Ensembl

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Apoptosis, Biological rhythms, Cell cycle, Cell division, Neurogenesis

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.11.22. 908.
    ReactomeiREACT_205490. DARPP-32 events.
    REACT_215067. Factors involved in megakaryocyte development and platelet production.
    REACT_217740. CRMPs in Sema3A signaling.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Cyclin-dependent-like kinase 5 (EC:2.7.11.1)
    Alternative name(s):
    Cell division protein kinase 5
    Proline-directed protein kinase 33 kDa subunit
    Short name:
    PDPK
    Serine/threonine-protein kinase PSSALRE
    Tau protein kinase II catalytic subunit
    Short name:
    TPKII catalytic subunit
    Gene namesi
    Name:CDK5
    Synonyms:CDKN5
    OrganismiBos taurus (Bovine)
    Taxonomic identifieri9913 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
    ProteomesiUP000009136: Chromosome 4

    Subcellular locationi

    Cytoplasm By similarity. Cell membrane By similarity; Peripheral membrane protein By similarity. Perikaryon By similarity. Cell projectionlamellipodium By similarity. Cell projectiongrowth cone By similarity. Nucleus By similarity. Cell junctionsynapsepostsynaptic cell membranepostsynaptic density By similarity
    Note: In axonal growth cone with extension to the peripheral lamellipodia By similarity. Under neurotoxic stress and neuronal injury conditions, CDK5R1 (p35) is cleaved by calpain to generate CDK5R1 (p25) in response to increased intracellular calcium. The elevated level of p25, when in complex with CDK5, leads to its subcellular misallocation as well as its hyperactivation. Colocalizes with CTNND2 in the cell body of neuronal cells, and with CTNNB1 in the cell-cell contacts and plasma membrane of undifferentiated and differentiated neuroblastoma cells. Reversibly attached to the plasma membrane in an inactive form when complexed to dephosphorylated p35 or CDK5R2 (p39), p35 phosphorylation releases this attachment and activates CDK5 By similarity.By similarity

    GO - Cellular componenti

    1. axon Source: AgBase
    2. cell junction Source: UniProtKB-KW
    3. cytoplasm Source: AgBase
    4. cytosol Source: AgBase
    5. dendrite Source: AgBase
    6. filopodium Source: AgBase
    7. growth cone Source: AgBase
    8. lamellipodium Source: AgBase
    9. membrane Source: AgBase
    10. neuromuscular junction Source: AgBase
    11. neuronal cell body Source: AgBase
    12. nucleus Source: AgBase
    13. perikaryon Source: UniProtKB-SubCell
    14. postsynaptic density Source: UniProtKB
    15. postsynaptic membrane Source: UniProtKB-KW

    Keywords - Cellular componenti

    Cell junction, Cell membrane, Cell projection, Cytoplasm, Membrane, Nucleus, Postsynaptic cell membrane, Synapse

    Pathology & Biotechi

    Keywords - Diseasei

    Neurodegeneration

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 292292Cyclin-dependent-like kinase 5PRO_0000085783Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei15 – 151Phosphotyrosine; by ABL1, EPHA4 and FYNBy similarity
    Modified residuei56 – 561N6-acetyllysineBy similarity
    Modified residuei72 – 721PhosphoserineBy similarity
    Modified residuei159 – 1591PhosphoserineBy similarity

    Post-translational modificationi

    Phosphorylation on Tyr-15 by ABL1 and FYN, and on Ser-159 by casein kinase 1 promotes kinase activity. By contrast, phosphorylation at Thr-14 inhibits activity By similarity.By similarity
    Phosphorylation at Ser-159 is essential for maximal catalytic activity.By similarity

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    PRIDEiQ02399.

    Interactioni

    Subunit structurei

    Heterodimer composed of a catalytic subunit CDK5 and a regulatory subunit CDK5R1 (p25) and macromolecular complex composed of at least CDK5, CDK5R1 (p35) and CDK5RAP1 or CDK5RAP2 or CDK5RAP3. Only the heterodimer shows kinase activity. Under neurotoxic stress and neuronal injury conditions, p35 is cleaved by calpain to generate p25 that hyperactivates CDK5, that becomes functionally disabled and often toxic. Found in a trimolecular complex with CABLES1 and ABL1. Interacts with CABLES1 and CABLES2 By similarity. Interacts with AATK and GSTP1. Binds to HDAC1 when in complex with p25. Interaction with myristoylation p35 promotes CDK5 association with membranes. Both isoforms 1 and 2 interacts with beta-catenin/CTNNB1. Interacts with delta-catenin/CTNND2 and APEX1. Interacts with P53/TP53 in neurons By similarity. Interacts with EPHA4; may mediate the activation of NGEF by EPHA4. Interacts with PTK2/FAK1. The complex p35/CDK5 interacts with CLOCK By similarity.By similarity

    Protein-protein interaction databases

    BioGridi158435. 1 interaction.
    IntActiQ02399. 3 interactions.

    Structurei

    3D structure databases

    ProteinModelPortaliQ02399.
    SMRiQ02399. Positions 1-292.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini4 – 286283Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00600000083998.
    HOGENOMiHOG000233024.
    HOVERGENiHBG014652.
    InParanoidiQ02399.
    KOiK02090.
    OMAiTMTKLPD.
    OrthoDBiEOG7966H8.
    TreeFamiTF101023.

    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.

    Q02399-1 [UniParc]FASTAAdd to Basket

    « Hide

    MQKYEKLEKI GEGTYGTVFK AKNRETHEIV ALKRVRLDDD DEGVPSSALR    50
    EICLLKELKH KNIVRLHDVL HSDKKLTLVF EFCDQDLKKY FDSCNGDLDP 100
    EIVKSFLFQL LKGLGFCHSR NVLHRDLKPQ NLLINRNGEL KLADFGLARA 150
    FGIPVRCYSA EVVTLWYRPP DVLFGAKLYS TSIDMWSAGC IFAELANAGR 200
    PLFPGNDVDD QLKRIFRLLG TPTEEQWPAM TKLPDYKPYP MYPATTSLVN 250
    VVPKLNATGR DLLQNLLKCN PVQRISAEEA LQHPYFSDFC PP 292
    Length:292
    Mass (Da):33,288
    Last modified:November 13, 2007 - v2
    Checksum:i4CB11CED9017D535
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti61 – 611K → E in AAI20084. 1 PublicationCurated
    Sequence conflicti151 – 1511F → L in AAI20084. 1 PublicationCurated
    Sequence conflicti169 – 1691P → S in AAA30606. (PubMed:1464604)Curated

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L04798 mRNA. Translation: AAA30606.1.
    X82440 mRNA. Translation: CAA57821.1.
    BC120083 mRNA. Translation: AAI20084.1.
    RefSeqiNP_776442.1. NM_174017.2.
    UniGeneiBt.51.

    Genome annotation databases

    EnsembliENSBTAT00000010212; ENSBTAP00000010212; ENSBTAG00000007766.
    GeneIDi281066.
    KEGGibta:281066.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    L04798 mRNA. Translation: AAA30606.1 .
    X82440 mRNA. Translation: CAA57821.1 .
    BC120083 mRNA. Translation: AAI20084.1 .
    RefSeqi NP_776442.1. NM_174017.2.
    UniGenei Bt.51.

    3D structure databases

    ProteinModelPortali Q02399.
    SMRi Q02399. Positions 1-292.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 158435. 1 interaction.
    IntActi Q02399. 3 interactions.

    Proteomic databases

    PRIDEi Q02399.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSBTAT00000010212 ; ENSBTAP00000010212 ; ENSBTAG00000007766 .
    GeneIDi 281066.
    KEGGi bta:281066.

    Organism-specific databases

    CTDi 1020.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00600000083998.
    HOGENOMi HOG000233024.
    HOVERGENi HBG014652.
    InParanoidi Q02399.
    KOi K02090.
    OMAi TMTKLPD.
    OrthoDBi EOG7966H8.
    TreeFami TF101023.

    Enzyme and pathway databases

    BRENDAi 2.7.11.22. 908.
    Reactomei REACT_205490. DARPP-32 events.
    REACT_215067. Factors involved in megakaryocyte development and platelet production.
    REACT_217740. CRMPs in Sema3A signaling.

    Miscellaneous databases

    NextBioi 20805147.

    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. "Brain proline-directed protein kinase is a neurofilament kinase which displays high sequence homology to p34cdc2."
      Lew J., Winkfein R.J., Paudel H.K., Wang J.H.
      J. Biol. Chem. 267:25922-25926(1992) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 14-20 AND 218-251.
      Tissue: Brain.
    2. "A cdc2-related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline-directed protein kinase associated with microtubule."
      Kobayashi S., Ishiguro K., Omori A., Takamatsu M., Arioka M., Imahori K., Uchida T.
      FEBS Lett. 335:171-175(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Tissue: Brain.
    3. NIH - Mammalian Gene Collection (MGC) project
      Submitted (AUG-2006) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Strain: Hereford.
      Tissue: Fetal cerebellum.

    Entry informationi

    Entry nameiCDK5_BOVIN
    AccessioniPrimary (citable) accession number: Q02399
    Secondary accession number(s): Q0VCN5, Q6LBE2
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: February 1, 1994
    Last sequence update: November 13, 2007
    Last modified: October 1, 2014
    This is version 132 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3