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Q15078 (CD5R1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 150. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Cyclin-dependent kinase 5 activator 1

Short name=CDK5 activator 1
Alternative name(s):
Cyclin-dependent kinase 5 regulatory subunit 1
TPKII regulatory subunit

Cleaved into the following 2 chains:

  1. Cyclin-dependent kinase 5 activator 1, p35
    Short name=p35
  2. Cyclin-dependent kinase 5 activator 1, p25
    Short name=p25
    Alternative name(s):
    Tau protein kinase II 23 kDa subunit
    Short name=p23
Gene names
Name:CDK5R1
Synonyms:CDK5R, NCK5A
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length307 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

p35 is a neuron specific activator of CDK5. The complex p35/CDK5 is required for neurite outgrowth and cortical lamination. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling. Activator of TPKII. 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. Ref.13

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. Interacts with EPHA4 and NGEF; may mediate the activation of NGEF by EPHA4 By similarity. Interacts with RASGRF2. The complex p35/CDK5 interacts with CLOCK. Ref.8 Ref.10 Ref.13

Subcellular location

Cyclin-dependent kinase 5 activator 1, p35: Cell membrane; Lipid-anchor; Cytoplasmic side Probable. Note: In the primary cortical neurons, p35 is present in the peripheries and nerve terminals. Ref.6 Ref.10 Ref.11

Cyclin-dependent kinase 5 activator 1, p25: Nucleus. Cytoplasmperinuclear region. Note: The conversion of p35 to p25 relocalizes the protein from the cell periphery to the cytoplasm, in nuclear and perinuclear regions. In the primary cortical neurons, p25 is primarily concentrated in the cell soma and is largely absent from neurites. Ref.6 Ref.10 Ref.11

Tissue specificity

Brain and neuron specific.

Post-translational modification

The p35 form is proteolytically cleaved by calpain, giving rise to the p25 form. P35 has a 5 to 10 fold shorter half-life compared to p25. The conversion results in deregulation of the CDK5 kinase: p25/CDK5 kinase displays an increased and altered tau phosphorylation in comparison to the p35/CDK5 kinase in vivo By similarity.

Myristoylated. A proper myristoylation signal is essential for the proper distribution of p35.

Ubiquitinated. Degradation of p35 by proteasome results in down-regulation of CDK5 activity. During this process, CDK5 phosphorylates p35 and induces its ubiquitination and subsequent degradation. Ref.7

Phosphorylation at Ser-8 and Thr-138 by CDK5 prevents calpain-mediated proteolysis.

Miscellaneous

Cleavage of p35 to p25 may be involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative diseases. The p25 form accumulates in neurons in the brain of patients with Alzheimer disease, but not in normal brain. This accumulation correlates with an increase in CDK5 kinase activity. Application of amyloid beta peptide A-beta(1-42) induced the conversion of p35 to p25 in primary cortical neurons. Expression of the p25/Cdk5 complex in cultured primary neurons induces cytoskeletal disruption, morphological degeneration and apoptosis.

Sequence similarities

Belongs to the cyclin-dependent kinase 5 activator family.

Ontologies

Keywords
   Biological processBiological rhythms
   Cellular componentCell membrane
Cytoplasm
Membrane
Nucleus
   PTMLipoprotein
Myristate
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processG-protein coupled acetylcholine receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

axon guidance

Inferred from sequence or structural similarity. Source: UniProtKB

axonal fasciculation

Inferred from sequence or structural similarity. Source: UniProtKB

brain development

Inferred from sequence or structural similarity. Source: UniProtKB

cell proliferation

Traceable author statement Ref.1. Source: ProtInc

cerebellum development

Inferred from electronic annotation. Source: Ensembl

embryo development

Inferred from sequence or structural similarity. Source: UniProtKB

ephrin receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

hippocampus development

Inferred from electronic annotation. Source: Ensembl

ionotropic glutamate receptor signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

layer formation in cerebral cortex

Inferred from electronic annotation. Source: Ensembl

negative regulation of axon extension

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription, DNA-templated

Inferred from mutant phenotype PubMed 20357208. Source: DFLAT

neuron cell-cell adhesion

Inferred from sequence or structural similarity. Source: UniProtKB

neuron differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

neuron migration

Inferred from sequence or structural similarity. Source: UniProtKB

neuron projection development

Inferred from sequence or structural similarity. Source: UniProtKB

peptidyl-serine phosphorylation

Inferred from direct assay PubMed 12832520. Source: UniProtKB

peptidyl-threonine phosphorylation

Inferred from direct assay PubMed 12832520. Source: UniProtKB

positive regulation of neuron apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of protein targeting to membrane

Inferred from electronic annotation. Source: Ensembl

regulation of actin cytoskeleton organization

Inferred from electronic annotation. Source: Ensembl

regulation of cyclin-dependent protein serine/threonine kinase activity

Traceable author statement PubMed 7592934. Source: ProtInc

regulation of dendritic spine morphogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of microtubule cytoskeleton organization

Inferred from electronic annotation. Source: Ensembl

regulation of neuron differentiation

Non-traceable author statement PubMed 10721722. Source: UniProtKB

rhythmic process

Inferred from electronic annotation. Source: UniProtKB-KW

serine phosphorylation of STAT3 protein

Inferred from electronic annotation. Source: Ensembl

superior olivary nucleus maturation

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentaxon

Inferred from sequence or structural similarity. Source: UniProtKB

contractile fiber

Inferred from sequence or structural similarity. Source: UniProtKB

cyclin-dependent protein kinase 5 holoenzyme complex

Inferred from electronic annotation. Source: InterPro

cytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

cytosol

Traceable author statement. Source: Reactome

dendrite

Inferred from sequence or structural similarity. Source: UniProtKB

dendritic spine

Inferred from sequence or structural similarity. Source: UniProtKB

growth cone

Inferred from sequence or structural similarity. Source: UniProtKB

membrane

Inferred from sequence or structural similarity. Source: UniProtKB

neuromuscular junction

Inferred from sequence or structural similarity. Source: UniProtKB

neuronal cell body

Inferred from sequence or structural similarity. Source: UniProtKB

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

perinuclear region of cytoplasm

Inferred from direct assay PubMed 12832520. Source: UniProtKB

plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

postsynaptic density

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functioncadherin binding

Inferred from sequence or structural similarity. Source: UniProtKB

calcium ion binding

Inferred from sequence or structural similarity. Source: UniProtKB

cyclin-dependent protein kinase 5 activator activity

Inferred from electronic annotation. Source: Ensembl

cyclin-dependent protein serine/threonine kinase activity

Inferred from electronic annotation. Source: Ensembl

kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 10721722PubMed 12223541. Source: UniProtKB

protein kinase activity

Traceable author statement PubMed 7592934. Source: ProtInc

protein kinase binding

Inferred from physical interaction PubMed 12832520. Source: UniProtKB

protein serine/threonine kinase activator activity

Inferred from direct assay PubMed 12832520. Source: UniProtKB

Complete GO annotation...

Binary interactions

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed
Chain2 – 307306Cyclin-dependent kinase 5 activator 1, p35
PRO_0000004794
Chain99 – 307209Cyclin-dependent kinase 5 activator 1, p25
PRO_0000004795

Sites

Site98 – 992Cleavage; by calpain By similarity

Amino acid modifications

Modified residue81Phosphoserine; by CDK5 Ref.9
Modified residue1381Phosphothreonine; by CDK5 Ref.9
Lipidation21N-myristoyl glycine Ref.11 Ref.12

Experimental info

Mutagenesis21G → A: Absent from the cell periphery. Ref.6 Ref.11
Mutagenesis81S → A: Increased susceptibility to calpain. Ref.9
Mutagenesis81S → E: Reduced susceptibility to calpain. Ref.9
Mutagenesis1381T → A: Increased susceptibility to calpain. Ref.9
Mutagenesis1381T → E: Reduced susceptibility to calpain. Ref.9

Secondary structure

................. 307
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q15078 [UniParc].

Last modified November 1, 1997. Version 1.
Checksum: D1C29A07AFF1B644

FASTA30734,060
        10         20         30         40         50         60 
MGTVLSLSPS YRKATLFEDG AATVGHYTAV QNSKNAKDKN LKRHSIISVL PWKRIVAVSA 

        70         80         90        100        110        120 
KKKNSKKVQP NSSYQNNITH LNNENLKKSL SCANLSTFAQ PPPAQPPAPP ASQLSGSQTG 

       130        140        150        160        170        180 
GSSSVKKAPH PAVTSAGTPK RVIVQASTSE LLRCLGEFLC RRCYRLKHLS PTDPVLWLRS 

       190        200        210        220        230        240 
VDRSLLLQGW QDQGFITPAN VVFLYMLCRD VISSEVGSDH ELQAVLLTCL YLSYSYMGNE 

       250        260        270        280        290        300 
ISYPLKPFLV ESCKEAFWDR CLSVINLMSS KMLQINADPH YFTQVFSDLK NESGQEDKKR 


LLLGLDR 

« Hide

References

« Hide 'large scale' references
[1]"p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5."
Tsai L.-H., Delalle I., Caviness V.S. Jr., Chae T., Harlow E.
Nature 371:419-423(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Brain.
[2]NIEHS SNPs program
Submitted (AUG-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Mammary gland.
[6]"Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration."
Patrick G.N., Zukerberg L., Nikolic M., de la Monte S., Dikkes P., Tsai L.H.
Nature 402:615-622(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF GLY-2, SUBCELLULAR LOCATION, INVOLVEMENT IN NEURODEGENERATIVE DISEASES.
[7]"Influence of phosphorylation of p35, an activator of cyclin-dependent kinase 5 (cdk5), on the proteolysis of p35."
Kerokoski P., Suuronen T., Salminen A., Soininen H., Pirttilae T.
Brain Res. Mol. Brain Res. 106:50-56(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION BY CDK5, UBIQUITINATION.
[8]"p35/cyclin-dependent kinase 5 phosphorylation of ras guanine nucleotide releasing factor 2 (RasGRF2) mediates Rac-dependent extracellular signal-regulated kinase 1/2 activity, altering RasGRF2 and microtubule-associated protein 1b distribution in neurons."
Kesavapany S., Amin N., Zheng Y.-L., Nijhara R., Jaffe H., Sihag R., Gutkind J.S., Takahashi S., Kulkarni A., Grant P., Pant H.C.
J. Neurosci. 24:4421-4431(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RASGRF2.
[9]"Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation."
Kamei H., Saito T., Ozawa M., Fujita Y., Asada A., Bibb J.A., Saido T.C., Sorimachi H., Hisanaga S.
J. Biol. Chem. 282:1687-1694(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-8 AND THR-138, MUTAGENESIS OF SER-8 AND THR-138.
[10]"Regulation of membrane association and kinase activity of Cdk5-p35 by phosphorylation of p35."
Sato K., Zhu Y.-S., Saito T., Yotsumoto K., Asada A., Hasegawa M., Hisanaga S.
J. Neurosci. Res. 85:3071-3078(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION BY CDK5, INTERACTION WITH CDK5, SUBCELLULAR LOCATION.
[11]"Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear localization of active cyclin-dependent kinase 5 complexes."
Asada A., Yamamoto N., Gohda M., Saito T., Hayashi N., Hisanaga S.
J. Neurochem. 106:1325-1336(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, MYRISTOYLATION, MUTAGENESIS OF GLY-2.
[12]"Strategy for comprehensive identification of human N-myristoylated proteins using an insect cell-free protein synthesis system."
Suzuki T., Moriya K., Nagatoshi K., Ota Y., Ezure T., Ando E., Tsunasawa S., Utsumi T.
Proteomics 10:1780-1793(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: MYRISTOYLATION AT GLY-2.
[13]"Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK protein by direct phosphorylation."
Kwak Y., Jeong J., Lee S., Park Y.U., Lee S.A., Han D.H., Kim J.H., Ohshima T., Mikoshiba K., Suh Y.H., Cho S., Park S.K.
J. Biol. Chem. 288:36878-36889(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH CLOCK.
[14]"Defining Cdk5 ligand chemical space with small molecule inhibitors of tau phosphorylation."
Ahn J.S., Radhakrishnan M.L., Mapelli M., Choi S., Tidor B., Cuny G.D., Musacchio A., Yeh L.A., Kosik K.S.
Chem. Biol. 12:811-823(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 145-293 IN COMPLEX WITH CDK5.
[15]"Mechanism of CDK5/p25 binding by CDK inhibitors."
Mapelli M., Massimiliano L., Crovace C., Seeliger M.A., Tsai L.H., Meijer L., Musacchio A.
J. Med. Chem. 48:671-679(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 100-307 IN COMPLEX WITH CDK5 AND INHIBITORS.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X80343 mRNA. Translation: CAA56587.1.
AY376350 Genomic DNA. Translation: AAQ74776.1.
BT019573 mRNA. Translation: AAV38380.1.
CH471147 Genomic DNA. Translation: EAW80227.1.
CH471147 Genomic DNA. Translation: EAW80228.1.
BC020580 mRNA. Translation: AAH20580.1.
CCDSCCDS11273.1.
PIRS50861.
RefSeqNP_003876.1. NM_003885.2.
UniGeneHs.500015.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1H4LX-ray2.65D/E147-293[»]
1UNGX-ray2.30D/E100-307[»]
1UNHX-ray2.35D/E100-307[»]
1UNLX-ray2.20D/E100-307[»]
3O0GX-ray1.95D/E145-293[»]
ProteinModelPortalQ15078.
SMRQ15078. Positions 145-293.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114376. 24 interactions.
DIPDIP-24222N.
IntActQ15078. 5 interactions.
MINTMINT-128009.
STRING9606.ENSP00000318486.

Chemistry

BindingDBQ15078.
ChEMBLCHEMBL1907600.

PTM databases

PhosphoSiteQ15078.

Polymorphism databases

DMDM2498217.

Proteomic databases

PaxDbQ15078.
PRIDEQ15078.

Protocols and materials databases

DNASU8851.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000313401; ENSP00000318486; ENSG00000176749.
GeneID8851.
KEGGhsa:8851.
UCSCuc002hhn.3. human.

Organism-specific databases

CTD8851.
GeneCardsGC17P030813.
HGNCHGNC:1775. CDK5R1.
MIM603460. gene.
neXtProtNX_Q15078.
PharmGKBPA26311.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG283789.
HOGENOMHOG000063677.
HOVERGENHBG050853.
InParanoidQ15078.
KOK11716.
OMACANLSSF.
OrthoDBEOG7GTT4Q.
PhylomeDBQ15078.
TreeFamTF101036.

Enzyme and pathway databases

ReactomeREACT_111045. Developmental Biology.
SignaLinkQ15078.

Gene expression databases

BgeeQ15078.
CleanExHS_CDK5R1.
GenevestigatorQ15078.

Family and domain databases

Gene3D1.10.472.10. 1 hit.
InterProIPR004944. CDK5_activator.
IPR013763. Cyclin-like.
[Graphical view]
PANTHERPTHR23401. PTHR23401. 1 hit.
PfamPF03261. CDK5_activator. 1 hit.
[Graphical view]
PIRSFPIRSF009324. Cdk5_activator. 1 hit.
SUPFAMSSF47954. SSF47954. 1 hit.
ProtoNetSearch...

Other

EvolutionaryTraceQ15078.
GeneWikiCDK5R1.
GenomeRNAi8851.
NextBio33227.
PMAP-CutDBQ15078.
PROQ15078.
SOURCESearch...

Entry information

Entry nameCD5R1_HUMAN
AccessionPrimary (citable) accession number: Q15078
Secondary accession number(s): E1P664, Q5U0G3
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1997
Last modified: July 9, 2014
This is version 150 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human chromosome 17

Human chromosome 17: entries, gene names and cross-references to MIM