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UniProtKB - Q16566 (KCC4_HUMAN)

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Protein

Calcium/calmodulin-dependent protein kinase type IV

Gene

CAMK4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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

View the complete GO annotation on QuickGO ...

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
View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionCalmodulin-binding, Kinase, Serine/threonine-protein kinase, Transferase
Biological processAdaptive immunity, Immunity, Inflammatory response
LigandATP-binding, Calcium, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.17 2681
ReactomeiR-HSA-111932 CaMK IV-mediated phosphorylation of CREB
R-HSA-2151201 Transcriptional activation of mitochondrial biogenesis
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 lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 5

Organism-specific databases

EuPathDBiHostDB:ENSG00000152495.10
HGNCiHGNC:1464 CAMK4
MIMi114080 gene
neXtProtiNX_Q16566

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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) threonine1 Publication1
Glycosylationi58O-linked (GlcNAc) serine1 Publication1
Glycosylationi137O-linked (GlcNAc) serine1 Publication1
Glycosylationi189O-linked (GlcNAc) serine1 Publication1
Modified residuei200Phosphothreonine; by CaMKK1 and CaMKK23 Publications1
Modified residuei336Phosphoserine; by autocatalysisBy similarity1
Modified residuei341PhosphoserineBy similarity1
Glycosylationi344O-linked (GlcNAc) serine1 Publication1
Glycosylationi345O-linked (GlcNAc) serine1 Publication1
Glycosylationi356O-linked (GlcNAc) serine1 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
ProteomicsDBi60921

PTM databases

iPTMnetiQ16566
PhosphoSitePlusiQ16566

Miscellaneous databases

PMAP-CutDBiQ16566

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

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi107264, 12 interactors
DIPiDIP-41997N
IntActiQ16566, 2 interactors
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

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

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

Phylogenomic databases

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

Family and domain databases

InterProiView protein in InterPro
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

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 → N1 PublicationCorresponds to variant dbSNP:rs35548075Ensembl.1
Natural variantiVAR_040606465Q → R1 PublicationCorresponds to variant dbSNP:rs56360861Ensembl.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

Similar proteinsi

Entry informationi

Entry nameiKCC4_HUMAN
AccessioniPrimary (citable) accession number: Q16566
Secondary accession number(s): D3DSZ7
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1996
Last modified: June 20, 2018
This is version 175 of the entry and version 1 of the sequence. See 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

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