CD5R1_RAT
ID CD5R1_RAT Reviewed; 307 AA.
AC P61810; Q62938;
DT 07-JUN-2004, integrated into UniProtKB/Swiss-Prot.
DT 07-JUN-2004, sequence version 1.
DT 03-AUG-2022, entry version 144.
DE RecName: Full=Cyclin-dependent kinase 5 activator 1;
DE Short=CDK5 activator 1;
DE AltName: Full=Cyclin-dependent kinase 5 regulatory subunit 1;
DE AltName: Full=TPKII regulatory subunit;
DE Contains:
DE RecName: Full=Cyclin-dependent kinase 5 activator 1, p35;
DE Short=p35;
DE Contains:
DE RecName: Full=Cyclin-dependent kinase 5 activator 1, p25;
DE Short=p25;
DE AltName: Full=Tau protein kinase II 23 kDa subunit;
DE Short=p23;
DE Flags: Precursor;
GN Name=Cdk5r1; Synonyms=Cdk5r;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=8662984; DOI=10.1074/jbc.271.24.14245;
RA Sun D., Leung C.L., Liem R.K.H.;
RT "Phosphorylation of the high molecular weight neurofilament protein (NF-H)
RT by Cdk5 and p35.";
RL J. Biol. Chem. 271:14245-14250(1996).
RN [2]
RP PROTEOLYTIC CLEAVAGE BY CALPAIN.
RX PubMed=10903889; DOI=10.1006/bbrc.2000.3070;
RA Nath R., Davis M., Probert A.W., Kupina N.C., Ren X., Schielke G.P.,
RA Wang K.K.;
RT "Processing of cdk5 activator p35 to its truncated form (p25) by calpain in
RT acutely injured neuronal cells.";
RL Biochem. Biophys. Res. Commun. 274:16-21(2000).
RN [3]
RP INTERACTION WITH RASGRF2.
RX PubMed=15128856; DOI=10.1523/jneurosci.0690-04.2004;
RA Kesavapany S., Amin N., Zheng Y.-L., Nijhara R., Jaffe H., Sihag R.,
RA Gutkind J.S., Takahashi S., Kulkarni A., Grant P., Pant H.C.;
RT "p35/cyclin-dependent kinase 5 phosphorylation of ras guanine nucleotide
RT releasing factor 2 (RasGRF2) mediates Rac-dependent extracellular signal-
RT regulated kinase 1/2 activity, altering RasGRF2 and microtubule-associated
RT protein 1b distribution in neurons.";
RL J. Neurosci. 24:4421-4431(2004).
RN [4]
RP PHOSPHORYLATION AT SER-8 AND THR-138, AND MUTAGENESIS OF THR-138.
RX PubMed=17121855; DOI=10.1074/jbc.m610541200;
RA Kamei H., Saito T., Ozawa M., Fujita Y., Asada A., Bibb J.A., Saido T.C.,
RA Sorimachi H., Hisanaga S.;
RT "Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25
RT by site-specific phosphorylation.";
RL J. Biol. Chem. 282:1687-1694(2007).
RN [5]
RP INTERACTION WITH EPHA4.
RX PubMed=17143272; DOI=10.1038/nn1811;
RA Fu W.Y., Chen Y., Sahin M., Zhao X.S., Shi L., Bikoff J.B., Lai K.O.,
RA Yung W.H., Fu A.K., Greenberg M.E., Ip N.Y.;
RT "Cdk5 regulates EphA4-mediated dendritic spine retraction through an
RT ephexin1-dependent mechanism.";
RL Nat. Neurosci. 10:67-76(2007).
CC -!- FUNCTION: p35 is a neuron specific activator of CDK5. The complex
CC p35/CDK5 is required for neurite outgrowth and cortical lamination.
CC Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4
CC signaling. Activator of TPKII. The complex p35/CDK5 participates in the
CC regulation of the circadian clock by modulating the function of CLOCK
CC protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates
CC the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer in
CC association with altered stability and subcellular distribution.
CC {ECO:0000250|UniProtKB:Q15078}.
CC -!- SUBUNIT: Heterodimer composed of a catalytic subunit CDK5 and a
CC regulatory subunit CDK5R1 (p25) and macromolecular complex composed of
CC at least CDK5, CDK5R1 (p35) and CDK5RAP1 or CDK5RAP2 or CDK5RAP3. Only
CC the heterodimer shows kinase activity (By similarity). Interacts with
CC EPHA4 and NGEF; may mediate the activation of NGEF by EPHA4
CC (PubMed:17143272). Interacts with RASGRF2 (PubMed:15128856). The
CC complex p35/CDK5 interacts with CLOCK (By similarity).
CC {ECO:0000250|UniProtKB:Q15078, ECO:0000269|PubMed:15128856,
CC ECO:0000269|PubMed:17143272}.
CC -!- INTERACTION:
CC P61810; Q03114: Cdk5; NbExp=3; IntAct=EBI-2008489, EBI-2008531;
CC P61810; B1WCA1: Fzr1; NbExp=3; IntAct=EBI-2008489, EBI-8078743;
CC -!- SUBCELLULAR LOCATION: [Cyclin-dependent kinase 5 activator 1, p35]:
CC Cell membrane {ECO:0000250|UniProtKB:Q15078}; Lipid-anchor
CC {ECO:0000250|UniProtKB:Q15078}; Cytoplasmic side
CC {ECO:0000250|UniProtKB:Q15078}. Cell projection, neuron projection
CC {ECO:0000250|UniProtKB:Q15078}. Note=In the primary cortical neurons,
CC p35 is present in the peripheries and nerve terminals.
CC {ECO:0000250|UniProtKB:Q15078}.
CC -!- SUBCELLULAR LOCATION: [Cyclin-dependent kinase 5 activator 1, p25]:
CC Nucleus {ECO:0000250|UniProtKB:Q15078}. Cytoplasm, perinuclear region
CC {ECO:0000250|UniProtKB:Q15078}. Perikaryon
CC {ECO:0000250|UniProtKB:Q15078}. Note=The conversion of p35 to p25
CC relocalizes the protein from the cell periphery to the cytoplasm, in
CC nuclear and perinuclear regions. In the primary cortical neurons, p25
CC is primarily concentrated in the cell soma and is largely absent from
CC neurites. {ECO:0000250|UniProtKB:Q15078}.
CC -!- TISSUE SPECIFICITY: Brain and neuron specific.
CC -!- PTM: The p35 form is proteolytically cleaved by calpain, giving rise to
CC the p25 form. P35 has a 5 to 10 fold shorter half-life compared to p25.
CC The conversion results in deregulation of the CDK5 kinase: p25/CDK5
CC kinase displays an increased and altered tau phosphorylation in
CC comparison to the p35/CDK5 kinase in vivo.
CC {ECO:0000269|PubMed:10903889, ECO:0000269|PubMed:17121855}.
CC -!- PTM: Myristoylated. A proper myristoylation signal is essential for the
CC proper distribution of p35 (By similarity).
CC {ECO:0000250|UniProtKB:Q15078}.
CC -!- PTM: Phosphorylation at Ser-8 and Thr-138 by CDK5 prevents calpain-
CC mediated proteolysis. {ECO:0000250|UniProtKB:Q15078}.
CC -!- PTM: Ubiquitinated, leading to its degradation: degradation of p35 by
CC proteasome results in down-regulation of CDK5 activity. During this
CC process, CDK5 phosphorylates p35 and induces its ubiquitination and
CC subsequent degradation. Ubiquitinated by the CRL2(FEM1B) complex, which
CC recognizes the -Gly-Leu-Asp-Arg C-degron at the C-terminus, leading to
CC its degradation. {ECO:0000250|UniProtKB:Q15078}.
CC -!- SIMILARITY: Belongs to the cyclin-dependent kinase 5 activator family.
CC {ECO:0000305}.
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DR EMBL; U50707; AAC52611.1; -; mRNA.
DR RefSeq; NP_446343.1; NM_053891.1.
DR AlphaFoldDB; P61810; -.
DR SMR; P61810; -.
DR BioGRID; 250555; 4.
DR CORUM; P61810; -.
DR DIP; DIP-29352N; -.
DR IntAct; P61810; 8.
DR MINT; P61810; -.
DR STRING; 10116.ENSRNOP00000062473; -.
DR iPTMnet; P61810; -.
DR PhosphoSitePlus; P61810; -.
DR PaxDb; P61810; -.
DR Ensembl; ENSRNOT00000119428; ENSRNOP00000079807; ENSRNOG00000068243.
DR GeneID; 116671; -.
DR KEGG; rno:116671; -.
DR CTD; 8851; -.
DR RGD; 629472; Cdk5r1.
DR eggNOG; KOG3932; Eukaryota.
DR GeneTree; ENSGT00390000008812; -.
DR HOGENOM; CLU_034132_2_0_1; -.
DR InParanoid; P61810; -.
DR OMA; EVATDHE; -.
DR OrthoDB; 1492547at2759; -.
DR PhylomeDB; P61810; -.
DR TreeFam; TF101036; -.
DR Reactome; R-RNO-399956; CRMPs in Sema3A signaling.
DR Reactome; R-RNO-6804756; Regulation of TP53 Activity through Phosphorylation.
DR PRO; PR:P61810; -.
DR Proteomes; UP000002494; Chromosome 10.
DR Bgee; ENSRNOG00000021685; Expressed in frontal cortex and 14 other tissues.
DR Genevisible; P61810; RN.
DR GO; GO:0030424; C:axon; IDA:UniProtKB.
DR GO; GO:0043292; C:contractile fiber; IDA:UniProtKB.
DR GO; GO:0000307; C:cyclin-dependent protein kinase holoenzyme complex; ISO:RGD.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0030425; C:dendrite; IDA:UniProtKB.
DR GO; GO:0043197; C:dendritic spine; IDA:UniProtKB.
DR GO; GO:0030426; C:growth cone; IDA:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0031594; C:neuromuscular junction; IDA:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0014069; C:postsynaptic density; IDA:UniProtKB.
DR GO; GO:0098793; C:presynapse; IDA:SynGO.
DR GO; GO:0016533; C:protein kinase 5 complex; IDA:RGD.
DR GO; GO:0003779; F:actin binding; ISO:RGD.
DR GO; GO:0051015; F:actin filament binding; ISO:RGD.
DR GO; GO:0045296; F:cadherin binding; IDA:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR GO; GO:0061575; F:cyclin-dependent protein serine/threonine kinase activator activity; IDA:RGD.
DR GO; GO:0046875; F:ephrin receptor binding; IPI:UniProtKB.
DR GO; GO:0035255; F:ionotropic glutamate receptor binding; ISO:RGD.
DR GO; GO:0016301; F:kinase activity; IDA:UniProtKB.
DR GO; GO:0002020; F:protease binding; ISO:RGD.
DR GO; GO:0019901; F:protein kinase binding; IPI:RGD.
DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; IDA:UniProtKB.
DR GO; GO:0048675; P:axon extension; TAS:UniProtKB.
DR GO; GO:0007411; P:axon guidance; ISS:UniProtKB.
DR GO; GO:0007413; P:axonal fasciculation; ISS:UniProtKB.
DR GO; GO:0007420; P:brain development; IEP:RGD.
DR GO; GO:0021549; P:cerebellum development; ISO:RGD.
DR GO; GO:0021799; P:cerebral cortex radially oriented cell migration; ISO:RGD.
DR GO; GO:0009792; P:embryo development ending in birth or egg hatching; IDA:UniProtKB.
DR GO; GO:0048013; P:ephrin receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0007213; P:G protein-coupled acetylcholine receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0070315; P:G1 to G0 transition involved in cell differentiation; ISO:RGD.
DR GO; GO:0021766; P:hippocampus development; ISO:RGD.
DR GO; GO:0035235; P:ionotropic glutamate receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0021819; P:layer formation in cerebral cortex; ISO:RGD.
DR GO; GO:0030517; P:negative regulation of axon extension; ISO:RGD.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISO:RGD.
DR GO; GO:0007158; P:neuron cell-cell adhesion; ISS:UniProtKB.
DR GO; GO:0030182; P:neuron differentiation; IDA:UniProtKB.
DR GO; GO:0001764; P:neuron migration; ISS:UniProtKB.
DR GO; GO:0031175; P:neuron projection development; IMP:UniProtKB.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; ISO:RGD.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISO:RGD.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IDA:UniProtKB.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; ISO:RGD.
DR GO; GO:0090314; P:positive regulation of protein targeting to membrane; ISO:RGD.
DR GO; GO:2000273; P:positive regulation of signaling receptor activity; ISO:RGD.
DR GO; GO:0032956; P:regulation of actin cytoskeleton organization; ISO:RGD.
DR GO; GO:0061001; P:regulation of dendritic spine morphogenesis; ISS:UniProtKB.
DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; ISO:RGD.
DR GO; GO:0098693; P:regulation of synaptic vesicle cycle; IDA:SynGO.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR GO; GO:0042501; P:serine phosphorylation of STAT protein; ISO:RGD.
DR GO; GO:0021722; P:superior olivary nucleus maturation; ISO:RGD.
DR InterPro; IPR004944; CDK5_activator.
DR InterPro; IPR036915; Cyclin-like_sf.
DR PANTHER; PTHR23401; PTHR23401; 1.
DR Pfam; PF03261; CDK5_activator; 1.
DR PIRSF; PIRSF009324; Cdk5_activator; 1.
DR SUPFAM; SSF47954; SSF47954; 1.
PE 1: Evidence at protein level;
KW Biological rhythms; Cell membrane; Cell projection; Cytoplasm; Lipoprotein;
KW Membrane; Myristate; Nucleus; Phosphoprotein; Reference proteome;
KW Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q15078"
FT CHAIN 2..307
FT /note="Cyclin-dependent kinase 5 activator 1, p35"
FT /id="PRO_0000004798"
FT CHAIN 99..307
FT /note="Cyclin-dependent kinase 5 activator 1, p25"
FT /id="PRO_0000004799"
FT REGION 97..133
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 111..129
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 98..99
FT /note="Cleavage; by calpain"
FT /evidence="ECO:0000269|PubMed:10903889"
FT MOD_RES 8
FT /note="Phosphoserine; by CDK5"
FT /evidence="ECO:0000250|UniProtKB:Q15078"
FT MOD_RES 138
FT /note="Phosphothreonine; by CDK5"
FT /evidence="ECO:0000250|UniProtKB:Q15078"
FT LIPID 2
FT /note="N-myristoyl glycine"
FT /evidence="ECO:0000250"
FT MUTAGEN 138
FT /note="T->A: Increased susceptibility to calpain cleavage."
FT /evidence="ECO:0000269|PubMed:17121855"
FT MUTAGEN 138
FT /note="T->E: Decreased susceptibility to calpain cleavage."
FT /evidence="ECO:0000269|PubMed:17121855"
SQ SEQUENCE 307 AA; 34031 MW; 165AA0747410B0C0 CRC64;
MGTVLSLSPS YRKATLFEDG AATVGHYTAV QNSKNAKDKN LKRHSIISVL PWKRIVAVSA
KKKNSKKAQP NSSYQSNIAH LNNENLKKSL SCANLSTFAQ PPPAQPPAPP ASQLSGSQTG
VSSSVKKAPH PAITSAGTPK RVIVQASTSE LLRCLGEFLC RRCYRLKHLS PTDPVLWLRS
VDRSLLLQGW QDQGFITPAN VVFLYMLCRD VISSEVGSDH ELQAVLLTCL YLSYSYMGNE
ISYPLKPFLV ESCKEAFWDR CLSVINLMSS KMLQINADPH YFTQVFSDLK NESGQEDKKR
LLLGLDR
