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Q15078

- CD5R1_HUMAN

UniProt

Q15078 - CD5R1_HUMAN

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Protein

Cyclin-dependent kinase 5 activator 1

Gene

CDK5R1

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei98 – 992Cleavage; by calpainBy similarity

GO - Molecular functioni

  1. cadherin binding Source: UniProtKB
  2. calcium ion binding Source: UniProtKB
  3. cyclin-dependent protein kinase 5 activator activity Source: Ensembl
  4. cyclin-dependent protein serine/threonine kinase activity Source: Ensembl
  5. kinase activity Source: UniProtKB
  6. protein kinase activity Source: ProtInc
  7. protein kinase binding Source: UniProtKB
  8. protein serine/threonine kinase activator activity Source: UniProtKB

GO - Biological processi

  1. axonal fasciculation Source: UniProtKB
  2. axon guidance Source: UniProtKB
  3. brain development Source: UniProtKB
  4. cell proliferation Source: ProtInc
  5. cerebellum development Source: Ensembl
  6. embryo development Source: Ensembl
  7. ephrin receptor signaling pathway Source: UniProtKB
  8. G-protein coupled acetylcholine receptor signaling pathway Source: UniProtKB
  9. hippocampus development Source: Ensembl
  10. ionotropic glutamate receptor signaling pathway Source: UniProtKB
  11. layer formation in cerebral cortex Source: Ensembl
  12. negative regulation of axon extension Source: Ensembl
  13. negative regulation of transcription, DNA-templated Source: DFLAT
  14. neuron cell-cell adhesion Source: UniProtKB
  15. neuron differentiation Source: UniProtKB
  16. neuron migration Source: UniProtKB
  17. neuron projection development Source: UniProtKB
  18. peptidyl-serine phosphorylation Source: UniProtKB
  19. peptidyl-threonine phosphorylation Source: UniProtKB
  20. positive regulation of neuron apoptotic process Source: UniProtKB
  21. positive regulation of protein targeting to membrane Source: Ensembl
  22. regulation of actin cytoskeleton organization Source: Ensembl
  23. regulation of cyclin-dependent protein serine/threonine kinase activity Source: ProtInc
  24. regulation of dendritic spine morphogenesis Source: UniProtKB
  25. regulation of microtubule cytoskeleton organization Source: Ensembl
  26. regulation of neuron differentiation Source: UniProtKB
  27. rhythmic process Source: UniProtKB-KW
  28. serine phosphorylation of STAT3 protein Source: Ensembl
  29. superior olivary nucleus maturation Source: Ensembl
Complete GO annotation...

Keywords - Biological processi

Biological rhythms

Enzyme and pathway databases

ReactomeiREACT_19199. CRMPs in Sema3A signaling.
SignaLinkiQ15078.

Names & Taxonomyi

Protein namesi
Recommended 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:
Alternative name(s):
Tau protein kinase II 23 kDa subunit
Short name:
p23
Gene namesi
Name:CDK5R1
Synonyms:CDK5R, NCK5A
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 17

Organism-specific databases

HGNCiHGNC:1775. CDK5R1.

Subcellular locationi

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

GO - Cellular componenti

  1. axon Source: UniProtKB
  2. contractile fiber Source: UniProtKB
  3. cyclin-dependent protein kinase 5 holoenzyme complex Source: InterPro
  4. cytoplasm Source: UniProtKB
  5. cytosol Source: Reactome
  6. dendrite Source: UniProtKB
  7. dendritic spine Source: UniProtKB
  8. growth cone Source: UniProtKB
  9. membrane Source: UniProtKB
  10. neuromuscular junction Source: UniProtKB
  11. neuronal cell body Source: UniProtKB
  12. nucleus Source: UniProtKB
  13. perinuclear region of cytoplasm Source: UniProtKB
  14. plasma membrane Source: UniProtKB-KW
  15. postsynaptic density Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi2 – 21G → A: Absent from the cell periphery. 2 Publications
Mutagenesisi8 – 81S → A: Increased susceptibility to calpain. 1 Publication
Mutagenesisi8 – 81S → E: Reduced susceptibility to calpain. 1 Publication
Mutagenesisi138 – 1381T → A: Increased susceptibility to calpain. 1 Publication
Mutagenesisi138 – 1381T → E: Reduced susceptibility to calpain. 1 Publication

Organism-specific databases

PharmGKBiPA26311.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed
Chaini2 – 307306Cyclin-dependent kinase 5 activator 1, p35PRO_0000004794Add
BLAST
Chaini99 – 307209Cyclin-dependent kinase 5 activator 1, p25PRO_0000004795Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Lipidationi2 – 21N-myristoyl glycine1 Publication
Modified residuei8 – 81Phosphoserine; by CDK51 Publication
Modified residuei138 – 1381Phosphothreonine; by CDK51 Publication

Post-translational modificationi

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).By similarity
Myristoylated. A proper myristoylation signal is essential for the proper distribution of p35.2 Publications
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.1 Publication
Phosphorylation at Ser-8 and Thr-138 by CDK5 prevents calpain-mediated proteolysis.1 Publication

Keywords - PTMi

Lipoprotein, Myristate, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ15078.
PRIDEiQ15078.

PTM databases

PhosphoSiteiQ15078.

Miscellaneous databases

PMAP-CutDBQ15078.

Expressioni

Tissue specificityi

Brain and neuron specific.

Gene expression databases

BgeeiQ15078.
CleanExiHS_CDK5R1.
GenevestigatoriQ15078.

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. 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.By similarity5 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
AATKQ6ZMQ8-12EBI-746189,EBI-2008436
AATKQ6ZMQ8-26EBI-746189,EBI-2008441
CDK5Q005356EBI-746189,EBI-1041567

Protein-protein interaction databases

BioGridi114376. 29 interactions.
DIPiDIP-24222N.
IntActiQ15078. 8 interactions.
MINTiMINT-128009.
STRINGi9606.ENSP00000318486.

Structurei

Secondary structure

1
307
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi148 – 16215
Helixi172 – 18716
Helixi198 – 21114
Helixi219 – 23719
Beta strandi239 – 2413
Helixi246 – 2483
Helixi254 – 27724
Helixi279 – 29012

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
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[»]
ProteinModelPortaliQ15078.
SMRiQ15078. Positions 145-293.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ15078.

Family & Domainsi

Sequence similaritiesi

Phylogenomic databases

eggNOGiNOG283789.
GeneTreeiENSGT00390000008812.
HOGENOMiHOG000063677.
HOVERGENiHBG050853.
InParanoidiQ15078.
KOiK11716.
OMAiCANLSSF.
OrthoDBiEOG7GTT4Q.
PhylomeDBiQ15078.
TreeFamiTF101036.

Family and domain databases

Gene3Di1.10.472.10. 1 hit.
InterProiIPR004944. CDK5_activator.
IPR013763. Cyclin-like.
[Graphical view]
PANTHERiPTHR23401. PTHR23401. 1 hit.
PfamiPF03261. CDK5_activator. 1 hit.
[Graphical view]
PIRSFiPIRSF009324. Cdk5_activator. 1 hit.
SUPFAMiSSF47954. SSF47954. 1 hit.

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q15078-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MGTVLSLSPS YRKATLFEDG AATVGHYTAV QNSKNAKDKN LKRHSIISVL
60 70 80 90 100
PWKRIVAVSA KKKNSKKVQP NSSYQNNITH LNNENLKKSL SCANLSTFAQ
110 120 130 140 150
PPPAQPPAPP ASQLSGSQTG GSSSVKKAPH PAVTSAGTPK RVIVQASTSE
160 170 180 190 200
LLRCLGEFLC RRCYRLKHLS PTDPVLWLRS VDRSLLLQGW QDQGFITPAN
210 220 230 240 250
VVFLYMLCRD VISSEVGSDH ELQAVLLTCL YLSYSYMGNE ISYPLKPFLV
260 270 280 290 300
ESCKEAFWDR CLSVINLMSS KMLQINADPH YFTQVFSDLK NESGQEDKKR

LLLGLDR
Length:307
Mass (Da):34,060
Last modified:November 1, 1997 - v1
Checksum:iD1C29A07AFF1B644
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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.
CCDSiCCDS11273.1.
PIRiS50861.
RefSeqiNP_003876.1. NM_003885.2.
UniGeneiHs.500015.

Genome annotation databases

EnsembliENST00000313401; ENSP00000318486; ENSG00000176749.
GeneIDi8851.
KEGGihsa:8851.
UCSCiuc002hhn.3. human.

Polymorphism databases

DMDMi2498217.

Cross-referencesi

Web resourcesi

NIEHS-SNPs

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
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 .
CCDSi CCDS11273.1.
PIRi S50861.
RefSeqi NP_003876.1. NM_003885.2.
UniGenei Hs.500015.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
1H4L X-ray 2.65 D/E 147-293 [» ]
1UNG X-ray 2.30 D/E 100-307 [» ]
1UNH X-ray 2.35 D/E 100-307 [» ]
1UNL X-ray 2.20 D/E 100-307 [» ]
3O0G X-ray 1.95 D/E 145-293 [» ]
ProteinModelPortali Q15078.
SMRi Q15078. Positions 145-293.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 114376. 29 interactions.
DIPi DIP-24222N.
IntActi Q15078. 8 interactions.
MINTi MINT-128009.
STRINGi 9606.ENSP00000318486.

Chemistry

BindingDBi Q15078.
ChEMBLi CHEMBL2783.

PTM databases

PhosphoSitei Q15078.

Polymorphism databases

DMDMi 2498217.

Proteomic databases

PaxDbi Q15078.
PRIDEi Q15078.

Protocols and materials databases

DNASUi 8851.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000313401 ; ENSP00000318486 ; ENSG00000176749 .
GeneIDi 8851.
KEGGi hsa:8851.
UCSCi uc002hhn.3. human.

Organism-specific databases

CTDi 8851.
GeneCardsi GC17P030813.
HGNCi HGNC:1775. CDK5R1.
MIMi 603460. gene.
neXtProti NX_Q15078.
PharmGKBi PA26311.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG283789.
GeneTreei ENSGT00390000008812.
HOGENOMi HOG000063677.
HOVERGENi HBG050853.
InParanoidi Q15078.
KOi K11716.
OMAi CANLSSF.
OrthoDBi EOG7GTT4Q.
PhylomeDBi Q15078.
TreeFami TF101036.

Enzyme and pathway databases

Reactomei REACT_19199. CRMPs in Sema3A signaling.
SignaLinki Q15078.

Miscellaneous databases

EvolutionaryTracei Q15078.
GeneWikii CDK5R1.
GenomeRNAii 8851.
NextBioi 33227.
PMAP-CutDB Q15078.
PROi Q15078.
SOURCEi Search...

Gene expression databases

Bgeei Q15078.
CleanExi HS_CDK5R1.
Genevestigatori Q15078.

Family and domain databases

Gene3Di 1.10.472.10. 1 hit.
InterProi IPR004944. CDK5_activator.
IPR013763. Cyclin-like.
[Graphical view ]
PANTHERi PTHR23401. PTHR23401. 1 hit.
Pfami PF03261. CDK5_activator. 1 hit.
[Graphical view ]
PIRSFi PIRSF009324. Cdk5_activator. 1 hit.
SUPFAMi SSF47954. SSF47954. 1 hit.
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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. 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. Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 100-307 IN COMPLEX WITH CDK5 AND INHIBITORS.

Entry informationi

Entry nameiCD5R1_HUMAN
AccessioniPrimary (citable) accession number: Q15078
Secondary accession number(s): E1P664, Q5U0G3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1997
Last modified: October 29, 2014
This is version 153 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

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.

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 17
    Human chromosome 17: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3