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P08414 (KCC4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified March 19, 2014. Version 140. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Calcium/calmodulin-dependent protein kinase type IV

Short name=CaMK IV
EC=2.7.11.17
Alternative name(s):
CaM kinase-GR
Gene names
Name:Camk4
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length469 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK4 signaling cascade and regulates, mainly by phosphorylation, the activity of several transcription activators, such as CREB1, MEF2D, JUN and RORA, which play pivotal roles in immune response, inflammation, and memory consolidation. In the thymus, regulates the CD4+/CD8+ double positive thymocytes selection threshold during T-cell ontogeny. In CD4 memory T-cells, is required to link T-cell antigen receptor (TCR) signaling to the production of IL2, IFNG and IL4 (through the regulation of CREB and MEF2). Regulates the differentiation and survival phases of osteoclasts and dendritic cells (DCs). Mediates DCs survival by linking TLR4 and the regulation of temporal expression of BCL2. Phosphorylates the transcription activator CREB1 on 'Ser-133' in hippocampal neuron nuclei and contribute to memory consolidation and long term potentiation (LTP) in the hippocampus. Can activate the MAP kinases MAPK1/ERK2, MAPK8/JNK1 and MAPK14/p38 and stimulate transcription through the phosphorylation of ELK1 and ATF2. Can also phosphorylate in vitro CREBBP, PRM2, MEF2A and STMN1/OP18 By similarity. May be involved in spermatogenesis. Ref.4 Ref.5 Ref.6 Ref.7 Ref.9

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

Activated by Ca2+/calmodulin. Binding of calmodulin results in conformational change that relieves intrasteric autoinhibition and allows phosphorylation of Thr-196 within the activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-196 results in a 10-20-fold increase in total activity to generate Ca2+/calmodulin-independent activity. Autophosphorylation of the N-terminus Ser-11 and Ser-12 is required for full activation. Inactivated by protein phosphatase 2A (PPP2CA/PPP2CB) which dephosphorylates Thr-196, thereby terminating autonomous activity and helping to maintain the enzyme in its autoinhibited state.

Subunit structure

Monomer By similarity. Interacts with protein phosphatase 2A (PPP2CA/PPP2CB); the interaction is mutually exclusive with binding to Ca2+/calmodulin By similarity.

Subcellular location

Cytoplasm. Nucleus. Note: Localized in hippocampal neuron nuclei By similarity. In spermatids, associated with chromatin and nuclear matrix. Ref.6

Tissue specificity

Expressed in brain and testis. Ref.6 Ref.8

Domain

The autoinhibitory domain overlaps with the calmodulin binding region and interacts in the inactive folded state with the catalytic domain as a pseudosubstrate By similarity.

Post-translational modification

Phosphorylated by CaMKK1 and CaMKK2 on Thr-196. Dephosphorylated by protein phosphatase 2A. Autophosphorylated on Ser-11 and Ser-12 By similarity.

Glycosylation at Ser-185 modulates the phosphorylation of CaMK4 at Thr-196 and negatively regulates its activity toward CREB1 in basal conditions and during early inomycin stimulation By similarity.

Disruption phenotype

Male mice are infertile with impairment of spermiogenesis in late elongating spermatids. The sequential deposition of sperm basic nuclear proteins on chromatin is disrupted, with a specific loss of protamine-2 and prolonged retention of Tnp2 in step-15 spermatids. Ref.6

Sequence similarities

Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily.

Contains 1 protein kinase domain.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 469469Calcium/calmodulin-dependent protein kinase type IV
PRO_0000086107

Regions

Domain42 – 296255Protein kinase
Nucleotide binding48 – 569ATP By similarity
Region297 – 33640Autoinhibitory domain By similarity
Region302 – 31918PP2A-binding By similarity
Region318 – 33720Calmodulin-binding Potential

Sites

Active site1601Proton acceptor By similarity
Binding site711ATP By similarity

Amino acid modifications

Modified residue111Phosphoserine; by autocatalysis By similarity
Modified residue121Phosphoserine; by autocatalysis By similarity
Modified residue1961Phosphothreonine; by CaMKK1 and CaMKK2 By similarity
Modified residue3321Phosphoserine; by autocatalysis By similarity
Glycosylation531O-linked (GlcNAc) By similarity
Glycosylation541O-linked (GlcNAc) By similarity
Glycosylation1331O-linked (GlcNAc) By similarity
Glycosylation1851O-linked (GlcNAc) By similarity
Glycosylation3401O-linked (GlcNAc) By similarity
Glycosylation3411O-linked (GlcNAc) By similarity
Glycosylation3521O-linked (GlcNAc) By similarity

Experimental info

Sequence conflict278 – 2803VLD → CFGI in AAA37366. Ref.2
Sequence conflict3021N → T in AAA37366. Ref.2

Sequences

Sequence LengthMass (Da)Tools
P08414 [UniParc].

Last modified April 1, 1993. Version 2.
Checksum: CE1F98670822F975

FASTA46952,628
        10         20         30         40         50         60 
MLKVTVPSCP SSPCSSVTAS TENLVPDYWI DGSNRDPLGD FFEVESELGR GATSIVYRCK 

        70         80         90        100        110        120 
QKGTQKPYAL KVLKKTVDKK IVRTEIGVLL RLSHPNIIKL KEIFETPTEI SLVLELVTGG 

       130        140        150        160        170        180 
ELFDRIVEKG YYSERDARDA VKQILEAVAY LHENGIVHRD LKPENLLYAT PAPDAPLKIA 

       190        200        210        220        230        240 
DFGLSKIVEH QVLMKTVCGT PGYCAPEILR GCAYGPEVDM WSVGIITYIL LCGFEPFYDE 

       250        260        270        280        290        300 
RGDQFMFRRI LNCEYYFISP WWDEVSLNAK DLVKKLIVLD PKKRLTTFQA LQHPWVTGKA 

       310        320        330        340        350        360 
ANFVHMDTAQ KKLQEFNARR KLKAAVKAVV ASSRLGSASS SHTSIQENHK ASSDPPSTQD 

       370        380        390        400        410        420 
AKDSTDLLGK KMQEEDQEED QVEAEASADE MRKLQSEEVE KDAGVKEEET SSMVPQDPED 

       430        440        450        460 
ELETDDPEMK RDSEEKLKSV EEEMDPMTEE EAPDAGLGVP QQDAIQPEY 

« Hide

References

[1]"cDNA sequence and differential expression of the mouse Ca2+/calmodulin-dependent protein kinase IV gene."
Jones D.A., Glod J., Wilson-Shaw D., Hahn W.E., Sikela J.M.
FEBS Lett. 289:105-109(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Strain: BALB/c.
Tissue: Brain.
[2]"Chromosomal localization of the human gene for brain Ca2+/calmodulin-dependent protein kinase type IV."
Sikela J.M., Law M.L., Kao F.-T., Hartz J.A., Wei Q., Hahn W.E.
Genomics 4:21-27(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 240-469.
[3]"Screening an expression library with a ligand probe: isolation and sequence of a cDNA corresponding to a brain calmodulin-binding protein."
Sikela J.M., Hahn W.E.
Proc. Natl. Acad. Sci. U.S.A. 84:3038-3042(1987) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 315-469.
Tissue: Brain.
[4]"Characterization of Ca2+/calmodulin-dependent protein kinase IV. Role in transcriptional regulation."
Enslen H., Sun P., Brickey D., Soderling S.H., Klamo E., Soderling T.R.
J. Biol. Chem. 269:15520-15527(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF CREB1.
[5]"CBP: a signal-regulated transcriptional coactivator controlled by nuclear calcium and CaM kinase IV."
Chawla S., Hardingham G.E., Quinn D.R., Bading H.
Science 281:1505-1509(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF CREBBP.
[6]"Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4."
Wu J.Y., Ribar T.J., Cummings D.E., Burton K.A., McKnight G.S., Means A.R.
Nat. Genet. 25:448-452(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF PRM2, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE.
[7]"An important role of neural activity-dependent CaMKIV signaling in the consolidation of long-term memory."
Kang H., Sun L.D., Atkins C.M., Soderling T.R., Wilson M.A., Tonegawa S.
Cell 106:771-783(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[8]"Regulation of mitochondrial biogenesis in skeletal muscle by CaMK."
Wu H., Kanatous S.B., Thurmond F.A., Gallardo T., Isotani E., Bassel-Duby R., Williams R.S.
Science 296:349-352(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[9]"Upregulation of calcium/calmodulin-dependent protein kinase IV improves memory formation and rescues memory loss with aging."
Fukushima H., Maeda R., Suzuki R., Suzuki A., Nomoto M., Toyoda H., Wu L.J., Xu H., Zhao M.G., Ueda K., Kitamoto A., Mamiya N., Yoshida T., Homma S., Masushige S., Zhuo M., Kida S.
J. Neurosci. 28:9910-9919(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M16206 mRNA. Translation: AAA39933.1.
M64266 mRNA. Translation: AAA37364.1.
J03057 mRNA. Translation: AAA37366.1.
X58995 mRNA. Translation: CAA41741.1.
PIRS17656.
UniGeneMm.222329.
Mm.410854.

3D structure databases

ProteinModelPortalP08414.
SMRP08414. Positions 30-388.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActP08414. 2 interactions.
MINTMINT-4099615.

PTM databases

PhosphoSiteP08414.

Proteomic databases

PaxDbP08414.
PRIDEP08414.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Organism-specific databases

MGIMGI:88258. Camk4.

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000233016.
HOVERGENHBG108055.
InParanoidP08414.

Enzyme and pathway databases

BRENDA2.7.11.17. 3474.

Gene expression databases

CleanExMM_CAMK4.
GenevestigatorP08414.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

PROP08414.
SOURCESearch...

Entry information

Entry nameKCC4_MOUSE
AccessionPrimary (citable) accession number: P08414
Secondary accession number(s): Q61381
Entry history
Integrated into UniProtKB/Swiss-Prot: August 1, 1988
Last sequence update: April 1, 1993
Last modified: March 19, 2014
This is version 140 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot