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MGP003718

UniProt Annotations

Entry Information
Gene Namecyclin-dependent kinase 5, regulatory subunit 1 (p35)
Protein EntryCD5R1_HUMAN
UniProt IDQ15078
SpeciesHuman
Comments
Comment typeDescription
Functionp35 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. {ECO:0000269|PubMed:24235147}.
InteractionQ6ZMQ8-1:AATK; NbExp=2; IntAct=EBI-746189, EBI-2008436; Q6ZMQ8-2:AATK; NbExp=6; IntAct=EBI-746189, EBI-2008441; Q00535:CDK5; NbExp=6; IntAct=EBI-746189, EBI-1041567;
MiscellaneousCleavage 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.
PtmMyristoylated. A proper myristoylation signal is essential for the proper distribution of p35. {ECO:0000269|PubMed:18507738, ECO:0000269|PubMed:20213681}.
PtmPhosphorylation at Ser-8 and Thr-138 by CDK5 prevents calpain-mediated proteolysis. {ECO:0000269|PubMed:17121855}.
PtmThe 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). {ECO:0000250}.
PtmUbiquitinated. 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. {ECO:0000269|PubMed:12393264}.
SimilarityBelongs to the cyclin-dependent kinase 5 activator family. {ECO:0000305}.
Subcellular LocationCyclin-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.
Subcellular LocationCyclin-dependent kinase 5 activator 1, p35: Cell membrane {ECO:0000305}; Lipid-anchor {ECO:0000305}; Cytoplasmic side {ECO:0000305}. Note=In the primary cortical neurons, p35 is present in the peripheries and nerve terminals.
SubunitHeterodimer 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. {ECO:0000250, ECO:0000269|PubMed:15128856, ECO:0000269|PubMed:15689152, ECO:0000269|PubMed:16039528, ECO:0000269|PubMed:17671990, ECO:0000269|PubMed:24235147}.
Tissue SpecificityBrain and neuron specific.
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/cdk5r1/";
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