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Q02399 (CDK5_BOVIN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 130. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Cyclin-dependent kinase 5

EC=2.7.11.22
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 names
Name:CDK5
Synonyms:CDKN5
OrganismBos taurus (Bovine) [Reference proteome]
Taxonomic identifier9913 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos

Protein attributes

Sequence length292 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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.

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

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.

Subunit structure

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.

Subcellular location

Cytoplasm By similarity. Cell membrane; 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.

Post-translational modification

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.

Phosphorylation at Ser-159 is essential for maximal catalytic activity By similarity.

Sequence similarities

Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processApoptosis
Biological rhythms
Cell cycle
Cell division
Neurogenesis
   Cellular componentCell junction
Cell membrane
Cell projection
Cytoplasm
Membrane
Nucleus
Postsynaptic cell membrane
Synapse
   DiseaseNeurodegeneration
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMAcetylation
Phosphoprotein
   Technical termComplete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processSchwann cell development

Inferred from electronic annotation. Source: Ensembl

axonogenesis

Inferred from sequence or structural similarity. Source: AgBase

behavioral response to cocaine

Inferred from electronic annotation. Source: Ensembl

calcium ion import

Inferred from electronic annotation. Source: Ensembl

cell division

Inferred from electronic annotation. Source: UniProtKB-KW

cell migration

Inferred from sequence or structural similarity. Source: AgBase

cell-matrix adhesion

Inferred from sequence or structural similarity. Source: AgBase

central nervous system neuron development

Inferred from electronic annotation. Source: Ensembl

cerebellar cortex formation

Inferred from electronic annotation. Source: Ensembl

corpus callosum development

Inferred from electronic annotation. Source: Ensembl

dendrite morphogenesis

Inferred from electronic annotation. Source: Ensembl

embryo development

Inferred from sequence or structural similarity. Source: AgBase

hippocampus development

Inferred from electronic annotation. Source: Ensembl

histone phosphorylation

Traceable author statement PubMed 8846918. Source: GOC

intracellular protein transport

Inferred from electronic annotation. Source: Ensembl

layer formation in cerebral cortex

Inferred from electronic annotation. Source: Ensembl

motor neuron axon guidance

Inferred from electronic annotation. Source: Ensembl

negative regulation of axon extension

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell cycle

Inferred from electronic annotation. Source: Ensembl

negative regulation of protein export from nucleus

Inferred from electronic annotation. Source: Ensembl

negative regulation of protein ubiquitination

Inferred from electronic annotation. Source: Ensembl

negative regulation of synaptic plasticity

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: Ensembl

neuron apoptotic process

Inferred from electronic annotation. Source: Ensembl

neuron differentiation

Inferred from sequence or structural similarity. Source: AgBase

neuron migration

Inferred from electronic annotation. Source: Ensembl

neuron projection development

Inferred from sequence or structural similarity. Source: AgBase

oligodendrocyte differentiation

Inferred from electronic annotation. Source: Ensembl

peptidyl-threonine phosphorylation

Inferred from electronic annotation. Source: Ensembl

positive regulation of calcium ion-dependent exocytosis

Inferred from electronic annotation. Source: Ensembl

positive regulation of neuron apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of protein binding

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein kinase activity

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein targeting to membrane

Inferred from electronic annotation. Source: Ensembl

positive regulation of receptor activity

Inferred from sequence or structural similarity. Source: GOC

protein localization to synapse

Inferred from electronic annotation. Source: Ensembl

receptor catabolic process

Inferred from electronic annotation. Source: Ensembl

receptor clustering

Inferred from electronic annotation. Source: Ensembl

regulation of cell migration

Inferred from sequence or structural similarity. Source: AgBase

regulation of dendritic spine morphogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of excitatory postsynaptic membrane potential

Inferred from electronic annotation. Source: Ensembl

regulation of synaptic plasticity

Inferred from sequence or structural similarity. Source: UniProtKB

rhythmic process

Inferred from electronic annotation. Source: UniProtKB-KW

sensory perception of pain

Inferred from electronic annotation. Source: Ensembl

serine phosphorylation of STAT3 protein

Inferred from electronic annotation. Source: Ensembl

skeletal muscle tissue development

Inferred from electronic annotation. Source: Ensembl

synapse assembly

Inferred from electronic annotation. Source: Ensembl

synaptic transmission, dopaminergic

Inferred from electronic annotation. Source: Ensembl

synaptic transmission, glutamatergic

Inferred from electronic annotation. Source: Ensembl

visual learning

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentaxon

Inferred from sequence or structural similarity. Source: AgBase

cell junction

Inferred from electronic annotation. Source: UniProtKB-KW

cytoplasm

Inferred from sequence or structural similarity. Source: AgBase

cytosol

Inferred from sequence or structural similarity. Source: AgBase

dendrite

Inferred from sequence or structural similarity. Source: AgBase

filopodium

Inferred from sequence or structural similarity. Source: AgBase

growth cone

Inferred from sequence or structural similarity. Source: AgBase

lamellipodium

Inferred from sequence or structural similarity. Source: AgBase

membrane

Inferred from sequence or structural similarity. Source: AgBase

neuromuscular junction

Inferred from sequence or structural similarity. Source: AgBase

neuronal cell body

Inferred from sequence or structural similarity. Source: AgBase

nucleus

Inferred from sequence or structural similarity. Source: AgBase

perikaryon

Inferred from electronic annotation. Source: UniProtKB-SubCell

postsynaptic density

Inferred from sequence or structural similarity. Source: UniProtKB

postsynaptic membrane

Inferred from electronic annotation. Source: UniProtKB-KW

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

ErbB-2 class receptor binding

Inferred from sequence or structural similarity. Source: AgBase

ErbB-3 class receptor binding

Inferred from sequence or structural similarity. Source: UniProtKB

acetylcholine receptor activator activity

Inferred from sequence or structural similarity. Source: AgBase

cyclin-dependent protein serine/threonine kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

histone kinase activity

Traceable author statement PubMed 8846918. Source: UniProtKB

kinase activity

Inferred from sequence or structural similarity. Source: AgBase

protein serine/threonine kinase activity

Inferred from sequence or structural similarity. Source: AgBase

tau-protein kinase activity

Inferred from sequence or structural similarity. Source: AgBase

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 292292Cyclin-dependent kinase 5
PRO_0000085783

Regions

Domain4 – 286283Protein kinase
Nucleotide binding10 – 189ATP By similarity

Sites

Active site1261Proton acceptor By similarity
Binding site331ATP By similarity

Amino acid modifications

Modified residue151Phosphotyrosine; by ABL1, EPHA4 and FYN By similarity
Modified residue561N6-acetyllysine By similarity
Modified residue721Phosphoserine By similarity
Modified residue1591Phosphoserine By similarity

Experimental info

Sequence conflict611K → E in AAI20084. Ref.3
Sequence conflict1511F → L in AAI20084. Ref.3
Sequence conflict1691P → S in AAA30606. Ref.1

Sequences

Sequence LengthMass (Da)Tools
Q02399 [UniParc].

Last modified November 13, 2007. Version 2.
Checksum: 4CB11CED9017D535

FASTA29233,288
        10         20         30         40         50         60 
MQKYEKLEKI GEGTYGTVFK AKNRETHEIV ALKRVRLDDD DEGVPSSALR EICLLKELKH 

        70         80         90        100        110        120 
KNIVRLHDVL HSDKKLTLVF EFCDQDLKKY FDSCNGDLDP EIVKSFLFQL LKGLGFCHSR 

       130        140        150        160        170        180 
NVLHRDLKPQ NLLINRNGEL KLADFGLARA FGIPVRCYSA EVVTLWYRPP DVLFGAKLYS 

       190        200        210        220        230        240 
TSIDMWSAGC IFAELANAGR PLFPGNDVDD QLKRIFRLLG TPTEEQWPAM TKLPDYKPYP 

       250        260        270        280        290 
MYPATTSLVN VVPKLNATGR DLLQNLLKCN PVQRISAEEA LQHPYFSDFC PP 

« Hide

References

« Hide 'large scale' references
[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.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L04798 mRNA. Translation: AAA30606.1.
X82440 mRNA. Translation: CAA57821.1.
BC120083 mRNA. Translation: AAI20084.1.
RefSeqNP_776442.1. NM_174017.2.
UniGeneBt.51.

3D structure databases

ProteinModelPortalQ02399.
SMRQ02399. Positions 1-292.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid158435. 1 interaction.
IntActQ02399. 3 interactions.

Proteomic databases

PRIDEQ02399.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSBTAT00000010212; ENSBTAP00000010212; ENSBTAG00000007766.
GeneID281066.
KEGGbta:281066.

Organism-specific databases

CTD1020.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00600000083998.
HOGENOMHOG000233024.
HOVERGENHBG014652.
InParanoidQ02399.
KOK02090.
OMATMTKLPD.
OrthoDBEOG7966H8.
TreeFamTF101023.

Enzyme and pathway databases

BRENDA2.7.11.22. 908.

Family and domain databases

InterProIPR011009. 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]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio20805147.

Entry information

Entry nameCDK5_BOVIN
AccessionPrimary (citable) accession number: Q02399
Secondary accession number(s): Q0VCN5, Q6LBE2
Entry history
Integrated into UniProtKB/Swiss-Prot: February 1, 1994
Last sequence update: November 13, 2007
Last modified: July 9, 2014
This is version 130 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families