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Protein

Calcium/calmodulin-dependent protein kinase type IV

Gene

CAMK4

Organism
Homo sapiens (Human)
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/OP18.8 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-200 within the activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-200 results in a 10-20-fold increase in total activity to generate Ca2+/calmodulin-independent activity. Autophosphorylation of the N-terminus Ser-12 and Ser-13 is required for full activation. Inactivated by protein phosphatase 2A (PPP2CA/PPP2CB) which dephosphorylates Thr-200, thereby terminating autonomous activity and helping to maintain the enzyme in its autoinhibited state.3 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei75ATPPROSITE-ProRule annotation1
Active sitei164Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi52 – 60ATPPROSITE-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
  • peptidyl-serine phosphorylation Source: GO_Central
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • protein autophosphorylation Source: GO_Central
  • protein phosphorylation Source: ProtInc
  • regulation of osteoclast differentiation Source: UniProtKB
  • regulation of T cell differentiation in thymus Source: UniProtKB
  • signal transduction Source: ProtInc
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

BioCyciZFISH:HS07828-MONOMER.
BRENDAi2.7.11.17. 2681.
ReactomeiR-HSA-111932. CaMK IV-mediated phosphorylation of CREB.
R-HSA-442717. CREB phosphorylation through the activation of CaMKK.
R-HSA-442745. Activation of CaMK IV.
SignaLinkiQ16566.
SIGNORiQ16566.

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
Synonyms:CAMK, CAMK-GR, CAMKIV
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 5

Organism-specific databases

HGNCiHGNC:1464. CAMK4.

Subcellular locationi

  • Cytoplasm
  • Nucleus

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

GO - Cellular componenti

  • cytoplasm Source: GO_Central
  • cytosol Source: Reactome
  • extracellular exosome Source: UniProtKB
  • nucleolus Source: HPA
  • nucleoplasm Source: HPA
  • nucleus Source: GO_Central
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi12S → A: Loss of activity. 1 Publication1
Mutagenesisi13S → A: Loss of activity. 1 Publication1
Mutagenesisi57 – 58TS → AA: Loss of phosphorylation of CREB1. 1 Publication2
Mutagenesisi75K → E: Loss of activity; dominant negative form. 1 Publication1
Mutagenesisi189S → A: Increases phosphorylation of CREB1 2-fold. Decreases total O-linked glycosylation 2-fold. Increases ATP-binding affinity. 1 Publication1
Mutagenesisi200T → A: Loss of activation by CaMKK1 or CaMKK2. 1 Publication1
Mutagenesisi309 – 312HMDT → DEDD: Fully active Ca2+/CaM-independent kinase; when associated with 320-A-A-321. 1 Publication4
Mutagenesisi320 – 321FN → DD: Fully active Ca2+/CaM-independent kinase; when associated with 309-A--A-312. Loss of interaction with PPP2CA/PPP2CB. 2 Publications2

Organism-specific databases

DisGeNETi814.
OpenTargetsiENSG00000152495.
PharmGKBiPA26050.

Chemistry databases

ChEMBLiCHEMBL2494.
GuidetoPHARMACOLOGYi1955.

Polymorphism and mutation databases

BioMutaiCAMK4.
DMDMi2499586.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000861061 – 473Calcium/calmodulin-dependent protein kinase type IVAdd BLAST473

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei12Phosphoserine; by autocatalysis1 Publication1
Modified residuei13Phosphoserine; by autocatalysis1 Publication1
Glycosylationi57O-linked (GlcNAc)1 Publication1
Glycosylationi58O-linked (GlcNAc)1 Publication1
Glycosylationi137O-linked (GlcNAc)1 Publication1
Glycosylationi189O-linked (GlcNAc)1 Publication1
Modified residuei200Phosphothreonine; by CaMKK1 and CaMKK23 Publications1
Modified residuei336Phosphoserine; by autocatalysisBy similarity1
Modified residuei341PhosphoserineBy similarity1
Glycosylationi344O-linked (GlcNAc)1 Publication1
Glycosylationi345O-linked (GlcNAc)1 Publication1
Glycosylationi356O-linked (GlcNAc)1 Publication1
Modified residuei360PhosphoserineCombined sources1

Post-translational modificationi

Phosphorylated by CaMKK1 and CaMKK2 on Thr-200. Dephosphorylated by protein phosphatase 2A. Autophosphorylated on Ser-12 and Ser-13.3 Publications
Glycosylation at Ser-189 modulates the phosphorylation of CaMK4 at Thr-200 and negatively regulates its activity toward CREB1 in basal conditions and during early inomycin stimulation.3 Publications

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

EPDiQ16566.
MaxQBiQ16566.
PaxDbiQ16566.
PeptideAtlasiQ16566.
PRIDEiQ16566.

PTM databases

iPTMnetiQ16566.
PhosphoSitePlusiQ16566.

Miscellaneous databases

PMAP-CutDBQ16566.

Expressioni

Tissue specificityi

Expressed in brain, thymus, CD4 T-cells, testis and epithelial ovarian cancer tissue.3 Publications

Developmental stagei

Expressed during differentiation of monocyte-derived dendritic cells (at protein level).1 Publication

Gene expression databases

BgeeiENSG00000152495.
CleanExiHS_CAMK4.
ExpressionAtlasiQ16566. baseline and differential.
GenevisibleiQ16566. HS.

Organism-specific databases

HPAiCAB004347.
HPA011753.
HPA017206.

Interactioni

Subunit structurei

Monomer (By similarity). Interacts with protein phosphatase 2A (PPP2CA/PPP2CB); the interaction is mutually exclusive with binding to Ca2+/calmodulin.By similarity2 Publications

GO - Molecular functioni

Protein-protein interaction databases

BioGridi107264. 12 interactors.
DIPiDIP-41997N.
IntActiQ16566. 1 interactor.
MINTiMINT-192934.
STRINGi9606.ENSP00000282356.

Chemistry databases

BindingDBiQ16566.

Structurei

Secondary structure

1473
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi36 – 38Combined sources3
Helixi42 – 44Combined sources3
Beta strandi46 – 54Combined sources9
Beta strandi56 – 65Combined sources10
Turni66 – 68Combined sources3
Beta strandi71 – 78Combined sources8
Helixi91 – 95Combined sources5
Beta strandi104 – 109Combined sources6
Beta strandi111 – 118Combined sources8
Helixi126 – 130Combined sources5
Helixi138 – 157Combined sources20
Helixi167 – 169Combined sources3
Beta strandi170 – 176Combined sources7
Beta strandi181 – 183Combined sources3
Helixi205 – 207Combined sources3
Helixi210 – 213Combined sources4
Helixi221 – 236Combined sources16
Helixi247 – 255Combined sources9
Turni263 – 268Combined sources6
Helixi271 – 278Combined sources8
Helixi285 – 287Combined sources3
Helixi291 – 296Combined sources6
Turni298 – 301Combined sources4
Helixi311 – 335Combined sources25

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2W4OX-ray2.17A15-340[»]
ProteinModelPortaliQ16566.
SMRiQ16566.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ16566.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini46 – 300Protein kinasePROSITE-ProRule annotationAdd BLAST255

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni305 – 321Autoinhibitory domainAdd BLAST17
Regioni306 – 323PP2A-bindingAdd BLAST18
Regioni322 – 341Calmodulin-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.1 Publication

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0032. Eukaryota.
ENOG410XRMJ. LUCA.
GeneTreeiENSGT00760000118944.
HOGENOMiHOG000233016.
HOVERGENiHBG108055.
InParanoidiQ16566.
KOiK05869.
OMAiQQDVILP.
OrthoDBiEOG091G0HK9.
PhylomeDBiQ16566.
TreeFamiTF351230.

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.

Q16566-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLKVTVPSCS ASSCSSVTAS AAPGTASLVP DYWIDGSNRD ALSDFFEVES
60 70 80 90 100
ELGRGATSIV YRCKQKGTQK PYALKVLKKT VDKKIVRTEI GVLLRLSHPN
110 120 130 140 150
IIKLKEIFET PTEISLVLEL VTGGELFDRI VEKGYYSERD AADAVKQILE
160 170 180 190 200
AVAYLHENGI VHRDLKPENL LYATPAPDAP LKIADFGLSK IVEHQVLMKT
210 220 230 240 250
VCGTPGYCAP EILRGCAYGP EVDMWSVGII TYILLCGFEP FYDERGDQFM
260 270 280 290 300
FRRILNCEYY FISPWWDEVS LNAKDLVRKL IVLDPKKRLT TFQALQHPWV
310 320 330 340 350
TGKAANFVHM DTAQKKLQEF NARRKLKAAV KAVVASSRLG SASSSHGSIQ
360 370 380 390 400
ESHKASRDPS PIQDGNEDMK AIPEGEKIQG DGAQAAVKGA QAELMKVQAL
410 420 430 440 450
EKVKGADINA EEAPKMVPKA VEDGIKVADL ELEEGLAEEK LKTVEEAAAP
460 470
REGQGSSAVG FEVPQQDVIL PEY
Length:473
Mass (Da):51,926
Last modified:November 1, 1996 - v1
Checksum:iEFEE51E5612326DC
GO

Sequence cautioni

The sequence AAH16695 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_040604150E → G in a lung adenocarcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_040605178D → N.1 PublicationCorresponds to variant rs35548075dbSNPEnsembl.1
Natural variantiVAR_040606465Q → R.1 PublicationCorresponds to variant rs56360861dbSNPEnsembl.1
Natural variantiVAR_040607469I → M in a lung large cell carcinoma sample; somatic mutation. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D30742 mRNA. Translation: BAA06403.1.
L17000 mRNA. Translation: AAA35639.1.
L24959 mRNA. Translation: AAA18251.1.
CH471086 Genomic DNA. Translation: EAW49033.1.
CH471086 Genomic DNA. Translation: EAW49034.1.
BC016695 mRNA. Translation: AAH16695.2. Different initiation.
BC025687 mRNA. Translation: AAH25687.1.
CCDSiCCDS4103.1.
PIRiA53036.
RefSeqiNP_001310303.1. NM_001323374.1.
NP_001310304.1. NM_001323375.1.
NP_001735.1. NM_001744.5.
UniGeneiHs.438801.
Hs.591269.

Genome annotation databases

EnsembliENST00000282356; ENSP00000282356; ENSG00000152495.
ENST00000512453; ENSP00000422634; ENSG00000152495.
GeneIDi814.
KEGGihsa:814.
UCSCiuc003kpf.4. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D30742 mRNA. Translation: BAA06403.1.
L17000 mRNA. Translation: AAA35639.1.
L24959 mRNA. Translation: AAA18251.1.
CH471086 Genomic DNA. Translation: EAW49033.1.
CH471086 Genomic DNA. Translation: EAW49034.1.
BC016695 mRNA. Translation: AAH16695.2. Different initiation.
BC025687 mRNA. Translation: AAH25687.1.
CCDSiCCDS4103.1.
PIRiA53036.
RefSeqiNP_001310303.1. NM_001323374.1.
NP_001310304.1. NM_001323375.1.
NP_001735.1. NM_001744.5.
UniGeneiHs.438801.
Hs.591269.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2W4OX-ray2.17A15-340[»]
ProteinModelPortaliQ16566.
SMRiQ16566.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107264. 12 interactors.
DIPiDIP-41997N.
IntActiQ16566. 1 interactor.
MINTiMINT-192934.
STRINGi9606.ENSP00000282356.

Chemistry databases

BindingDBiQ16566.
ChEMBLiCHEMBL2494.
GuidetoPHARMACOLOGYi1955.

PTM databases

iPTMnetiQ16566.
PhosphoSitePlusiQ16566.

Polymorphism and mutation databases

BioMutaiCAMK4.
DMDMi2499586.

Proteomic databases

EPDiQ16566.
MaxQBiQ16566.
PaxDbiQ16566.
PeptideAtlasiQ16566.
PRIDEiQ16566.

Protocols and materials databases

DNASUi814.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000282356; ENSP00000282356; ENSG00000152495.
ENST00000512453; ENSP00000422634; ENSG00000152495.
GeneIDi814.
KEGGihsa:814.
UCSCiuc003kpf.4. human.

Organism-specific databases

CTDi814.
DisGeNETi814.
GeneCardsiCAMK4.
HGNCiHGNC:1464. CAMK4.
HPAiCAB004347.
HPA011753.
HPA017206.
MIMi114080. gene.
neXtProtiNX_Q16566.
OpenTargetsiENSG00000152495.
PharmGKBiPA26050.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0032. Eukaryota.
ENOG410XRMJ. LUCA.
GeneTreeiENSGT00760000118944.
HOGENOMiHOG000233016.
HOVERGENiHBG108055.
InParanoidiQ16566.
KOiK05869.
OMAiQQDVILP.
OrthoDBiEOG091G0HK9.
PhylomeDBiQ16566.
TreeFamiTF351230.

Enzyme and pathway databases

BioCyciZFISH:HS07828-MONOMER.
BRENDAi2.7.11.17. 2681.
ReactomeiR-HSA-111932. CaMK IV-mediated phosphorylation of CREB.
R-HSA-442717. CREB phosphorylation through the activation of CaMKK.
R-HSA-442745. Activation of CaMK IV.
SignaLinkiQ16566.
SIGNORiQ16566.

Miscellaneous databases

ChiTaRSiCAMK4. human.
EvolutionaryTraceiQ16566.
GeneWikiiCAMK4.
GenomeRNAii814.
PMAP-CutDBQ16566.
PROiQ16566.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000152495.
CleanExiHS_CAMK4.
ExpressionAtlasiQ16566. baseline and differential.
GenevisibleiQ16566. HS.

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_HUMAN
AccessioniPrimary (citable) accession number: Q16566
Secondary accession number(s): D3DSZ7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1996
Last modified: November 2, 2016
This is version 165 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 5
    Human chromosome 5: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. 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.