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Q02399

- CDK5_BOVIN

UniProt

Q02399 - CDK5_BOVIN

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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

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. protein localization to synapse Source: Ensembl
  36. receptor catabolic process Source: Ensembl
  37. receptor clustering Source: Ensembl
  38. regulation of cell migration Source: AgBase
  39. regulation of dendritic spine morphogenesis Source: UniProtKB
  40. regulation of excitatory postsynaptic membrane potential Source: Ensembl
  41. regulation of synaptic plasticity Source: UniProtKB
  42. rhythmic process Source: UniProtKB-KW
  43. Schwann cell development Source: Ensembl
  44. sensory perception of pain Source: Ensembl
  45. serine phosphorylation of STAT3 protein Source: Ensembl
  46. skeletal muscle tissue development Source: Ensembl
  47. synapse assembly Source: Ensembl
  48. synaptic transmission, dopaminergic Source: Ensembl
  49. synaptic transmission, glutamatergic Source: Ensembl
  50. visual learning Source: Ensembl
Complete GO annotation...

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. postsynaptic density Source: UniProtKB
  14. postsynaptic membrane Source: UniProtKB-KW
Complete GO annotation...

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.
GeneTreeiENSGT00760000119154.
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.
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

        10         20         30         40         50
MQKYEKLEKI GEGTYGTVFK AKNRETHEIV ALKRVRLDDD DEGVPSSALR
60 70 80 90 100
EICLLKELKH KNIVRLHDVL HSDKKLTLVF EFCDQDLKKY FDSCNGDLDP
110 120 130 140 150
EIVKSFLFQL LKGLGFCHSR NVLHRDLKPQ NLLINRNGEL KLADFGLARA
160 170 180 190 200
FGIPVRCYSA EVVTLWYRPP DVLFGAKLYS TSIDMWSAGC IFAELANAGR
210 220 230 240 250
PLFPGNDVDD QLKRIFRLLG TPTEEQWPAM TKLPDYKPYP MYPATTSLVN
260 270 280 290
VVPKLNATGR DLLQNLLKCN PVQRISAEEA LQHPYFSDFC PP
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 ENSGT00760000119154.
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.
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

« Hide 'large scale' publications
  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 29, 2014
This is version 133 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