Q15078 (CD5R1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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:

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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	307 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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.
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. Ref.8 Ref.10
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. 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. 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
Cellular component	Cell membrane Cytoplasm Membrane Nucleus
PTM	Lipoprotein Myristate Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	G-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: Compara 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: Compara ionotropic glutamate receptor signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB layer formation in cerebral cortex Inferred from electronic annotation. Source: Compara negative regulation of transcription, DNA-dependent Inferred from mutant phenotype PubMed 20357208. Source: DFLAT neuron cell-cell adhesion Inferred from sequence or structural similarity. Source: UniProtKB neuron migration 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: Compara regulation of actin cytoskeleton organization Inferred from electronic annotation. Source: Compara 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: Compara serine phosphorylation of STAT3 protein Inferred from electronic annotation. Source: Compara superior olivary nucleus maturation Inferred from electronic annotation. Source: Compara
Cellular_component	axon 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 cytosol Traceable author statement. Source: Reactome 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_function	cadherin 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: Compara cyclin-dependent protein serine/threonine kinase activity Inferred from electronic annotation. Source: Compara protein kinase activity Traceable author statement PubMed 7592934. Source: ProtInc protein serine/threonine kinase activator activity Inferred from direct assay PubMed 12832520. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
AATK	Q6ZMQ8-1	2	EBI-746189,EBI-2008436
AATK	Q6ZMQ8-2	6	EBI-746189,EBI-2008441
CDK5	Q00535	5	EBI-746189,EBI-1041567

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed

Chain

2 – 307

306

Cyclin-dependent kinase 5 activator 1, p35

PRO_0000004794

Chain

99 – 307

209

Cyclin-dependent kinase 5 activator 1, p25

PRO_0000004795

Sites

Site

98 – 99

2

Cleavage; by calpain By similarity

Amino acid modifications

Modified residue

8

1

Phosphoserine; by CDK5 Ref.9

Modified residue

138

1

Phosphothreonine; by CDK5 Ref.9

Lipidation

2

1

N-myristoyl glycine Ref.11 Ref.12

Experimental info

Mutagenesis

2

1

G → A: Absent from the cell periphery. Ref.6 Ref.11

Mutagenesis

8

1

S → A: Increased susceptibility to calpain. Ref.9

Mutagenesis

8

1

S → E: Reduced susceptibility to calpain. Ref.9

Mutagenesis

138

1

T → A: Increased susceptibility to calpain. Ref.9

Mutagenesis

138

1

T → E: Reduced susceptibility to calpain. Ref.9

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

307

Helix Strand Turn

Details...

Helix

148 – 162

15

Helix

172 – 187

16

Helix

198 – 211

14

Helix

219 – 237

19

Beta strand

239 – 241

3

Helix

246 – 248

3

Helix

254 – 277

24

Helix

279 – 290

12

Sequences

	Sequence		Length	Mass (Da)
	Q15078 [UniParc]. Last modified November 1, 1997. Version 1. Checksum: D1C29A07AFF1B644	FASTA	307	34,060
	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

References

	« Hide 'large scale' referencesShow '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. , 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]	"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.
[14]	"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

NIEHS-SNPs

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.

IPI

IPI00014316.

PIR

S50861.

RefSeq

NP_003876.1. NM_003885.2.

UniGene

Hs.500015.

3D structure databases

PDBe
RCSB PDB
PDBj

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	[»]

ProteinModelPortal

Q15078.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-24222N.

IntAct

Q15078. 5 interactions.

STRING

9606.ENSP00000318486.

PTM databases

PhosphoSite

Q15078.

Polymorphism databases

DMDM

2498217.

Proteomic databases

PaxDb

Q15078.

PRIDE

Q15078.

Protocols and materials databases

DNASU

8851.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000313401; ENSP00000318486; ENSG00000176749.

GeneID

8851.

KEGG

hsa:8851.

UCSC

uc002hhn.3. human.

Organism-specific databases

CTD

8851.

GeneCards

GC17P030813.

HGNC

HGNC:1775. CDK5R1.

MIM

603460. gene.

neXtProt

NX_Q15078.

PharmGKB

PA26311.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG283789.

HOGENOM

HOG000063677.

HOVERGEN

HBG050853.

InParanoid

Q15078.

KO

K11716.

OMA

WDRCLSI.

OrthoDB

EOG49PB00.

PhylomeDB

Q15078.

Enzyme and pathway databases

Pathway_Interaction_DB

lis1pathway. Lissencephaly gene (LIS1) in neuronal migration and development.
reelinpathway. Reelin signaling pathway.
mapktrkpathway. Trk receptor signaling mediated by the MAPK pathway.

Reactome

REACT_111045. Developmental Biology.

Gene expression databases

Bgee

Q15078.

CleanEx

HS_CDK5R1.

Genevestigator

Q15078.

GermOnline

ENSG00000176749. Homo sapiens.

Family and domain databases

Gene3D

1.10.472.10. 1 hit.

InterPro

IPR004944. CDK5_activator.
IPR013763. Cyclin-like.
[Graphical view]

PANTHER

PTHR23401. PTHR23401. 1 hit.

Pfam

PF03261. CDK5_activator. 1 hit.
[Graphical view]

PIRSF

PIRSF009324. Cdk5_activator. 1 hit.

SUPFAM

SSF47954. Cyclin_like. 1 hit.

ProtoNet

Search...

Other

BindingDB

Q15078.

ChEMBL

CHEMBL2783.

EvolutionaryTrace

Q15078.

GenomeRNAi

8851.

NextBio

33227.

PMAP-CutDB

Q15078.

SOURCE

Search...

Entry information

Entry name

CD5R1_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 137 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.