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P08414

- KCC4_MOUSE

UniProt

P08414 - KCC4_MOUSE

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Protein

Calcium/calmodulin-dependent protein kinase type IV

Gene

Camk4

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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.By similarity5 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

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.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei71 – 711ATPPROSITE-ProRule annotation
Active sitei160 – 1601Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi48 – 569ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. calmodulin-dependent protein kinase activity Source: MGI

GO - Biological processi

  1. inflammatory response Source: UniProtKB-KW
  2. long-term memory Source: UniProtKB
  3. myeloid dendritic cell differentiation Source: UniProtKB
  4. neuron-neuron synaptic transmission Source: MGI
  5. nucleocytoplasmic transport Source: MGI
  6. positive regulation of protein export from nucleus Source: MGI
  7. positive regulation of transcription, DNA-templated Source: MGI
  8. protein phosphorylation Source: MGI
  9. signal transduction Source: MGI
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Adaptive immunity, Immunity, Inflammatory response

Keywords - Ligandi

ATP-binding, Calcium, Calmodulin-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.17. 3474.

Names & Taxonomyi

Protein namesi
Recommended name:
Calcium/calmodulin-dependent protein kinase type IV (EC:2.7.11.17)
Short name:
CaMK IV
Alternative name(s):
CaM kinase-GR
Gene namesi
Name:Camk4
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Unplaced

Organism-specific databases

MGIiMGI:88258. Camk4.

Subcellular locationi

Cytoplasm 1 Publication. Nucleus 1 Publication
Note: Localized in hippocampal neuron nuclei (By similarity). In spermatids, associated with chromatin and nuclear matrix.By similarity

GO - Cellular componenti

  1. cytoplasm Source: MGI
  2. nucleus Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Disruption phenotypei

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.1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 469469Calcium/calmodulin-dependent protein kinase type IVPRO_0000086107Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei11 – 111Phosphoserine; by autocatalysisBy similarity
Modified residuei12 – 121Phosphoserine; by autocatalysisBy similarity
Glycosylationi53 – 531O-linked (GlcNAc)By similarity
Glycosylationi54 – 541O-linked (GlcNAc)By similarity
Glycosylationi133 – 1331O-linked (GlcNAc)By similarity
Glycosylationi185 – 1851O-linked (GlcNAc)By similarity
Modified residuei196 – 1961Phosphothreonine; by CaMKK1 and CaMKK2By similarity
Modified residuei332 – 3321Phosphoserine; by autocatalysisBy similarity
Glycosylationi340 – 3401O-linked (GlcNAc)By similarity
Glycosylationi341 – 3411O-linked (GlcNAc)By similarity
Glycosylationi352 – 3521O-linked (GlcNAc)By similarity

Post-translational modificationi

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

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

MaxQBiP08414.
PaxDbiP08414.
PRIDEiP08414.

PTM databases

PhosphoSiteiP08414.

Expressioni

Tissue specificityi

Expressed in brain and testis.2 Publications

Gene expression databases

CleanExiMM_CAMK4.
GenevestigatoriP08414.

Interactioni

Subunit structurei

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

Protein-protein interaction databases

IntActiP08414. 2 interactions.
MINTiMINT-4099615.

Structurei

3D structure databases

ProteinModelPortaliP08414.
SMRiP08414. Positions 30-388.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini42 – 296255Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni297 – 33640Autoinhibitory domainBy similarityAdd
BLAST
Regioni302 – 31918PP2A-bindingBy similarityAdd
BLAST
Regioni318 – 33720Calmodulin-bindingSequence AnalysisAdd
BLAST

Domaini

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

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
HOGENOMiHOG000233016.
HOVERGENiHBG108055.
InParanoidiP08414.
PhylomeDBiP08414.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P08414-1 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MLKVTVPSCP SSPCSSVTAS TENLVPDYWI DGSNRDPLGD FFEVESELGR
60 70 80 90 100
GATSIVYRCK QKGTQKPYAL KVLKKTVDKK IVRTEIGVLL RLSHPNIIKL
110 120 130 140 150
KEIFETPTEI SLVLELVTGG ELFDRIVEKG YYSERDARDA VKQILEAVAY
160 170 180 190 200
LHENGIVHRD LKPENLLYAT PAPDAPLKIA DFGLSKIVEH QVLMKTVCGT
210 220 230 240 250
PGYCAPEILR GCAYGPEVDM WSVGIITYIL LCGFEPFYDE RGDQFMFRRI
260 270 280 290 300
LNCEYYFISP WWDEVSLNAK DLVKKLIVLD PKKRLTTFQA LQHPWVTGKA
310 320 330 340 350
ANFVHMDTAQ KKLQEFNARR KLKAAVKAVV ASSRLGSASS SHTSIQENHK
360 370 380 390 400
ASSDPPSTQD AKDSTDLLGK KMQEEDQEED QVEAEASADE MRKLQSEEVE
410 420 430 440 450
KDAGVKEEET SSMVPQDPED ELETDDPEMK RDSEEKLKSV EEEMDPMTEE
460
EAPDAGLGVP QQDAIQPEY
Length:469
Mass (Da):52,628
Last modified:April 1, 1993 - v2
Checksum:iCE1F98670822F975
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti278 – 2803VLD → CFGI in AAA37366. (PubMed:2536634)Curated
Sequence conflicti302 – 3021N → T in AAA37366. (PubMed:2536634)Curated

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
M16206 mRNA. Translation: AAA39933.1.
M64266 mRNA. Translation: AAA37364.1.
J03057 mRNA. Translation: AAA37366.1.
X58995 mRNA. Translation: CAA41741.1.
CCDSiCCDS29122.1.
PIRiS17656.
UniGeneiMm.222329.
Mm.410854.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
M16206 mRNA. Translation: AAA39933.1 .
M64266 mRNA. Translation: AAA37364.1 .
J03057 mRNA. Translation: AAA37366.1 .
X58995 mRNA. Translation: CAA41741.1 .
CCDSi CCDS29122.1.
PIRi S17656.
UniGenei Mm.222329.
Mm.410854.

3D structure databases

ProteinModelPortali P08414.
SMRi P08414. Positions 30-388.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

IntActi P08414. 2 interactions.
MINTi MINT-4099615.

PTM databases

PhosphoSitei P08414.

Proteomic databases

MaxQBi P08414.
PaxDbi P08414.
PRIDEi P08414.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Organism-specific databases

MGIi MGI:88258. Camk4.

Phylogenomic databases

eggNOGi COG0515.
HOGENOMi HOG000233016.
HOVERGENi HBG108055.
InParanoidi P08414.
PhylomeDBi P08414.

Enzyme and pathway databases

BRENDAi 2.7.11.17. 3474.

Miscellaneous databases

PROi P08414.
SOURCEi Search...

Gene expression databases

CleanExi MM_CAMK4.
Genevestigatori P08414.

Family and domain databases

InterProi IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view ]
Pfami PF00069. Pkinase. 1 hit.
[Graphical view ]
SMARTi SM00220. S_TKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  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.

Entry informationi

Entry nameiKCC4_MOUSE
AccessioniPrimary (citable) accession number: P08414
Secondary accession number(s): Q61381
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 1, 1988
Last sequence update: April 1, 1993
Last modified: October 29, 2014
This is version 146 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3