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Protein

Calcium/calmodulin-dependent protein kinase type IV

Gene

Camk4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: 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)DescriptionActionsGraphical viewLength
Binding sitei71ATPPROSITE-ProRule annotation1
Active sitei160Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi48 – 56ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

  • adaptive immune response Source: UniProtKB-KW
  • inflammatory response Source: UniProtKB-KW
  • intracellular signal transduction Source: GO_Central
  • long-term memory Source: UniProtKB
  • myeloid dendritic cell differentiation Source: UniProtKB
  • neuron-neuron synaptic transmission Source: MGI
  • nucleocytoplasmic transport Source: MGI
  • peptidyl-serine phosphorylation Source: GO_Central
  • positive regulation of protein export from nucleus Source: MGI
  • positive regulation of transcription, DNA-templated Source: MGI
  • protein autophosphorylation Source: GO_Central
  • protein phosphorylation Source: MGI
  • 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
Proteomesi
  • UP000000589 Componenti: 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

  • cytoplasm Source: MGI
  • extracellular exosome Source: MGI
  • nucleolus Source: MGI
  • nucleoplasm Source: MGI
  • 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)DescriptionActionsGraphical viewLength
ChainiPRO_00000861071 – 469Calcium/calmodulin-dependent protein kinase type IVAdd BLAST469

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei11Phosphoserine; by autocatalysisBy similarity1
Modified residuei12Phosphoserine; by autocatalysisBy similarity1
Glycosylationi53O-linked (GlcNAc)By similarity1
Glycosylationi54O-linked (GlcNAc)By similarity1
Glycosylationi133O-linked (GlcNAc)By similarity1
Glycosylationi185O-linked (GlcNAc)By similarity1
Modified residuei196PhosphothreonineCombined sources1
Modified residuei332Phosphoserine; by autocatalysisBy similarity1
Modified residuei337PhosphoserineBy similarity1
Glycosylationi340O-linked (GlcNAc)By similarity1
Glycosylationi341O-linked (GlcNAc)By similarity1
Glycosylationi352O-linked (GlcNAc)By similarity1
Modified residuei433PhosphoserineBy similarity1
Modified residuei439PhosphoserineCombined sources1

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

EPDiP08414.
MaxQBiP08414.
PaxDbiP08414.
PeptideAtlasiP08414.
PRIDEiP08414.

PTM databases

iPTMnetiP08414.
PhosphoSitePlusiP08414.

Expressioni

Tissue specificityi

Expressed in brain and testis.2 Publications

Gene expression databases

CleanExiMM_CAMK4.

Interactioni

Subunit structurei

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

GO - Molecular functioni

Protein-protein interaction databases

IntActiP08414. 2 interactors.
MINTiMINT-4099615.
STRINGi10090.ENSMUSP00000046539.

Structurei

3D structure databases

ProteinModelPortaliP08414.
SMRiP08414.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini42 – 296Protein kinasePROSITE-ProRule annotationAdd BLAST255

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni297 – 336Autoinhibitory domainBy similarityAdd BLAST40
Regioni302 – 319PP2A-bindingBy similarityAdd BLAST18
Regioni318 – 337Calmodulin-bindingSequence analysisAdd BLAST20

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

eggNOGiKOG0032. Eukaryota.
ENOG410XRMJ. LUCA.
HOGENOMiHOG000233016.
HOVERGENiHBG108055.
InParanoidiP08414.
PhylomeDBiP08414.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
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)DescriptionActionsGraphical viewLength
Sequence conflicti278 – 280VLD → CFGI in AAA37366 (PubMed:2536634).Curated3
Sequence conflicti302N → T in AAA37366 (PubMed:2536634).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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:
EMBLi
GenBanki
DDBJi
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.

3D structure databases

ProteinModelPortaliP08414.
SMRiP08414.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiP08414. 2 interactors.
MINTiMINT-4099615.
STRINGi10090.ENSMUSP00000046539.

PTM databases

iPTMnetiP08414.
PhosphoSitePlusiP08414.

Proteomic databases

EPDiP08414.
MaxQBiP08414.
PaxDbiP08414.
PeptideAtlasiP08414.
PRIDEiP08414.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Organism-specific databases

MGIiMGI:88258. Camk4.

Phylogenomic databases

eggNOGiKOG0032. Eukaryota.
ENOG410XRMJ. LUCA.
HOGENOMiHOG000233016.
HOVERGENiHBG108055.
InParanoidiP08414.
PhylomeDBiP08414.

Enzyme and pathway databases

BRENDAi2.7.11.17. 3474.

Miscellaneous databases

PROiP08414.
SOURCEiSearch...

Gene expression databases

CleanExiMM_CAMK4.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
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]
ProtoNetiSearch...

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: November 2, 2016
This is version 161 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.