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UniProtKB - Q15078 (CD5R1_HUMAN)

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Protein

Cyclin-dependent kinase 5 activator 1

Gene

CDK5R1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: 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

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.

GO - Molecular functioni

  • cadherin binding Source: UniProtKB
  • calcium ion binding Source: UniProtKB
  • cyclin-dependent protein kinase 5 activator activity Source: Ensembl
  • ephrin receptor binding Source: Ensembl
  • kinase activity Source: UniProtKB
  • protein kinase activity Source: ProtInc
  • protein kinase binding Source: UniProtKB
  • protein serine/threonine kinase activator activity Source: UniProtKB
Complete GO annotation...

GO - Biological processi

Complete GO annotation...

Keywordsi

Biological processBiological rhythms

Enzyme and pathway databases

ReactomeiR-HSA-399956. CRMPs in Sema3A signaling.
R-HSA-6804756. Regulation of TP53 Activity through Phosphorylation.
R-HSA-8862803. Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models.
SignaLinkiQ15078.
SIGNORiQ15078.

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:
Cyclin-dependent kinase 5 activator 1, p35
Short name:
p35
Cyclin-dependent kinase 5 activator 1, p25
Short name:
p25
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 lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 17

Organism-specific databases

HGNCiHGNC:1775. CDK5R1.

Subcellular locationi

Cyclin-dependent kinase 5 activator 1, p35 :
Cyclin-dependent kinase 5 activator 1, p25 :
  • Nucleus
  • Cytoplasm › perinuclear 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

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi2G → A: Absent from the cell periphery. 2 Publications1
Mutagenesisi8S → A: Increased susceptibility to calpain. 1 Publication1
Mutagenesisi8S → E: Reduced susceptibility to calpain. 1 Publication1
Mutagenesisi138T → A: Increased susceptibility to calpain. 1 Publication1
Mutagenesisi138T → E: Reduced susceptibility to calpain. 1 Publication1

Organism-specific databases

DisGeNETi8851.
OpenTargetsiENSG00000176749.
PharmGKBiPA26311.

Chemistry databases

ChEMBLiCHEMBL2783.
DrugBankiDB02052. Indirubin-3'-Monoxime.

Polymorphism and mutation databases

BioMutaiCDK5R1.
DMDMi2498217.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemoved
ChainiPRO_00000047942 – 307Cyclin-dependent kinase 5 activator 1, p35Add BLAST306
ChainiPRO_000000479599 – 307Cyclin-dependent kinase 5 activator 1, p25Add BLAST209

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Lipidationi2N-myristoyl glycine1 Publication1
Modified residuei8Phosphoserine; by CDK51 Publication1
Modified residuei138Phosphothreonine; by CDK51 Publication1

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

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei98 – 99Cleavage; by calpainBy similarity2

Keywords - PTMi

Lipoprotein, Myristate, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ15078.
PaxDbiQ15078.
PeptideAtlasiQ15078.
PRIDEiQ15078.

PTM databases

iPTMnetiQ15078.
PhosphoSitePlusiQ15078.

Miscellaneous databases

PMAP-CutDBiQ15078.

Expressioni

Tissue specificityi

Brain and neuron specific.

Gene expression databases

BgeeiENSG00000176749.
CleanExiHS_CDK5R1.
ExpressionAtlasiQ15078. baseline and differential.
GenevisibleiQ15078. HS.

Organism-specific databases

HPAiHPA000252.

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

Show more details

GO - Molecular functioni

  • cadherin binding Source: UniProtKB
  • ephrin receptor binding Source: Ensembl
  • protein kinase binding Source: UniProtKB
Complete GO annotation...

Protein-protein interaction databases

BioGridi114376. 39 interactors.
DIPiDIP-24222N.
IntActiQ15078. 14 interactors.
MINTiMINT-128009.
STRINGi9606.ENSP00000318486.

Chemistry databases

BindingDBiQ15078.

Structurei

Secondary structure

1307
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi148 – 162Combined sources15
Helixi172 – 187Combined sources16
Helixi198 – 211Combined sources14
Helixi219 – 237Combined sources19
Beta strandi239 – 241Combined sources3
Helixi246 – 248Combined sources3
Helixi254 – 277Combined sources24
Helixi279 – 290Combined sources12

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ15078.

Family & Domainsi

Sequence similaritiesi

Belongs to the cyclin-dependent kinase 5 activator family.Curated

Phylogenomic databases

eggNOGiKOG3932. Eukaryota.
ENOG410YFUI. LUCA.
GeneTreeiENSGT00390000008812.
HOGENOMiHOG000063677.
HOVERGENiHBG050853.
InParanoidiQ15078.
KOiK11716.
OMAiLSIINLM.
OrthoDBiEOG091G0OB3.
PhylomeDBiQ15078.
TreeFamiTF101036.

Family and domain databases

Gene3Di1.10.472.10. 1 hit.
InterProiView protein in InterPro
IPR004944. CDK5_activator.
IPR013763. Cyclin-like.
PANTHERiPTHR23401. PTHR23401. 1 hit.
PfamiView protein in Pfam
PF03261. CDK5_activator. 1 hit.
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:
EMBLi
GenBanki
DDBJi
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.
XP_011523740.1. XM_011525438.2.
XP_016880770.1. XM_017025281.1.
UniGeneiHs.500015.

Genome annotation databases

EnsembliENST00000313401; ENSP00000318486; ENSG00000176749.
GeneIDi8851.
KEGGihsa:8851.
UCSCiuc002hhn.4. human.

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiCD5R1_HUMAN
AccessioniPrimary (citable) accession number: Q15078
Secondary accession number(s): E1P664, Q5U0G3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1997
Last modified: July 5, 2017
This is version 179 of the entry and version 1 of the sequence. See 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

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