UniProtKB - Q16566 (KCC4_HUMAN)
Calcium/calmodulin-dependent protein kinase type IV
CAMK4
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 PublicationsCatalytic activityi
Activity regulationi
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 75 | ATPPROSITE-ProRule annotation | 1 | |
Active sitei | 164 | Proton acceptorPROSITE-ProRule annotation | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 52 – 60 | ATPPROSITE-ProRule annotation | 9 |
GO - Molecular functioni
- ATP binding Source: UniProtKB-KW
- calcium-dependent protein serine/threonine kinase activity Source: GO_Central
- calmodulin binding Source: GO_Central
- calmodulin-dependent protein kinase activity Source: CACAO
- protein serine/threonine/tyrosine kinase activity Source: RHEA
- protein serine kinase activity Source: RHEA
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
Keywordsi
Molecular function | Calmodulin-binding, Kinase, Serine/threonine-protein kinase, Transferase |
Biological process | Adaptive immunity, Immunity, Inflammatory response |
Ligand | ATP-binding, Calcium, Nucleotide-binding |
Enzyme and pathway databases
BRENDAi | 2.7.11.17, 2681 |
PathwayCommonsi | Q16566 |
Reactomei | R-HSA-111932, CaMK IV-mediated phosphorylation of CREB R-HSA-2151201, Transcriptional activation of mitochondrial biogenesis R-HSA-442729, CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde R-HSA-9022535, Loss of phosphorylation of MECP2 at T308 R-HSA-9022692, Regulation of MECP2 expression and activity R-HSA-9617324, Negative regulation of NMDA receptor-mediated neuronal transmission |
SignaLinki | Q16566 |
SIGNORi | Q16566 |
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 |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:1464, CAMK4 |
MIMi | 114080, gene |
neXtProti | NX_Q16566 |
VEuPathDBi | HostDB:ENSG00000152495 |
Subcellular locationi
Extracellular region or secreted
- extracellular exosome Source: UniProtKB
Nucleus
- fibrillar center Source: HPA
- nucleoplasm Source: HPA
- nucleus Source: GO_Central
Other locations
- cytoplasm Source: GO_Central
- glutamatergic synapse Source: Ensembl
- postsynapse Source: Ensembl
Keywords - Cellular componenti
Cytoplasm, NucleusPathology & Biotechi
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 12 | S → A: Loss of activity. 1 Publication | 1 | |
Mutagenesisi | 13 | S → A: Loss of activity. 1 Publication | 1 | |
Mutagenesisi | 57 – 58 | TS → AA: Loss of phosphorylation of CREB1. 1 Publication | 2 | |
Mutagenesisi | 75 | K → E: Loss of activity; dominant negative form. 1 Publication | 1 | |
Mutagenesisi | 189 | S → A: Increases phosphorylation of CREB1 2-fold. Decreases total O-linked glycosylation 2-fold. Increases ATP-binding affinity. 1 Publication | 1 | |
Mutagenesisi | 200 | T → A: Loss of activation by CaMKK1 or CaMKK2. 1 Publication | 1 | |
Mutagenesisi | 309 – 312 | HMDT → DEDD: Fully active Ca2+/CaM-independent kinase; when associated with 320-A-A-321. 1 Publication | 4 | |
Mutagenesisi | 320 – 321 | FN → DD: Fully active Ca2+/CaM-independent kinase; when associated with 309-A--A-312. Loss of interaction with PPP2CA/PPP2CB. 2 Publications | 2 |
Organism-specific databases
DisGeNETi | 814 |
OpenTargetsi | ENSG00000152495 |
PharmGKBi | PA26050 |
Miscellaneous databases
Pharosi | Q16566, Tbio |
Chemistry databases
ChEMBLi | CHEMBL2494 |
DrugBanki | DB07676, 3-({[(3S)-3,4-dihydroxybutyl]oxy}amino)-1H,2'H-2,3'-biindol-2'-one DB07664, K-00546 |
DrugCentrali | Q16566 |
Genetic variation databases
BioMutai | CAMK4 |
DMDMi | 2499586 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000086106 | 1 – 473 | Calcium/calmodulin-dependent protein kinase type IVAdd BLAST | 473 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 12 | Phosphoserine; by autocatalysis1 Publication | 1 | |
Modified residuei | 13 | Phosphoserine; by autocatalysis1 Publication | 1 | |
Glycosylationi | 57 | O-linked (GlcNAc) threonine1 Publication | 1 | |
Glycosylationi | 58 | O-linked (GlcNAc) serine1 Publication | 1 | |
Glycosylationi | 137 | O-linked (GlcNAc) serine1 Publication | 1 | |
Glycosylationi | 189 | O-linked (GlcNAc) serine1 Publication | 1 | |
Modified residuei | 200 | Phosphothreonine; by CaMKK1 and CaMKK23 Publications | 1 | |
Modified residuei | 336 | Phosphoserine; by autocatalysisBy similarity | 1 | |
Modified residuei | 341 | PhosphoserineBy similarity | 1 | |
Glycosylationi | 344 | O-linked (GlcNAc) serine1 Publication | 1 | |
Glycosylationi | 345 | O-linked (GlcNAc) serine1 Publication | 1 | |
Glycosylationi | 356 | O-linked (GlcNAc) serine1 Publication | 1 | |
Modified residuei | 360 | PhosphoserineCombined sources | 1 |
Post-translational modificationi
Keywords - PTMi
Glycoprotein, PhosphoproteinProteomic databases
EPDi | Q16566 |
jPOSTi | Q16566 |
MassIVEi | Q16566 |
MaxQBi | Q16566 |
PaxDbi | Q16566 |
PeptideAtlasi | Q16566 |
PRIDEi | Q16566 |
ProteomicsDBi | 60921 |
PTM databases
GlyGeni | Q16566, 7 sites, 1 O-linked glycan (3 sites) |
iPTMneti | Q16566 |
MetOSitei | Q16566 |
PhosphoSitePlusi | Q16566 |
Expressioni
Tissue specificityi
Developmental stagei
Gene expression databases
Bgeei | ENSG00000152495, Expressed in caudate nucleus and 164 other tissues |
ExpressionAtlasi | Q16566, baseline and differential |
Genevisiblei | Q16566, HS |
Organism-specific databases
HPAi | ENSG00000152495, Group enriched (brain, lymphoid tissue) |
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 PublicationsGO - Molecular functioni
- calmodulin binding Source: GO_Central
Protein-protein interaction databases
BioGRIDi | 107264, 26 interactors |
DIPi | DIP-41997N |
IntActi | Q16566, 30 interactors |
STRINGi | 9606.ENSP00000282356 |
Chemistry databases
BindingDBi | Q16566 |
Miscellaneous databases
RNActi | Q16566, protein |
Structurei
Secondary structure
3D structure databases
AlphaFoldDBi | Q16566 |
SMRi | Q16566 |
ModBasei | Search... |
PDBe-KBi | Search... |
Miscellaneous databases
EvolutionaryTracei | Q16566 |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 46 – 300 | Protein kinasePROSITE-ProRule annotationAdd BLAST | 255 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 305 – 321 | Autoinhibitory domainAdd BLAST | 17 | |
Regioni | 306 – 323 | PP2A-bindingAdd BLAST | 18 | |
Regioni | 322 – 341 | Calmodulin-bindingSequence analysisAdd BLAST | 20 | |
Regioni | 341 – 368 | DisorderedSequence analysisAdd BLAST | 28 | |
Regioni | 445 – 473 | DisorderedSequence analysisAdd BLAST | 29 |
Compositional bias
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Compositional biasi | 351 – 368 | Basic and acidic residuesSequence analysisAdd BLAST | 18 |
Domaini
Sequence similaritiesi
Phylogenomic databases
eggNOGi | KOG0032, Eukaryota |
GeneTreei | ENSGT00940000160006 |
HOGENOMi | CLU_000288_63_0_1 |
InParanoidi | Q16566 |
OMAi | TKMVPEA |
OrthoDBi | 330091at2759 |
PhylomeDBi | Q16566 |
TreeFami | TF351230 |
Family and domain databases
InterProi | View protein in InterPro IPR011009, Kinase-like_dom_sf IPR000719, Prot_kinase_dom IPR017441, Protein_kinase_ATP_BS IPR008271, Ser/Thr_kinase_AS |
Pfami | View protein in Pfam PF00069, Pkinase, 1 hit |
SMARTi | View protein in SMART SM00220, S_TKc, 1 hit |
SUPFAMi | SSF56112, SSF56112, 1 hit |
PROSITEi | View protein in PROSITE PS00107, PROTEIN_KINASE_ATP, 1 hit PS50011, PROTEIN_KINASE_DOM, 1 hit PS00108, PROTEIN_KINASE_ST, 1 hit |
(1+)i Sequence
Sequence statusi: Complete.
This entry has 1 described isoform and 3 potential isoforms that are computationally mapped.Show allAlign All
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
Computationally mapped potential isoform sequencesi
There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketD6RE65 | D6RE65_HUMAN | Calcium/calmodulin-dependent protei... | CAMK4 | 142 | Annotation score: | ||
D6REY7 | D6REY7_HUMAN | Calcium/calmodulin-dependent protei... | CAMK4 | 109 | Annotation score: | ||
D6RCD6 | D6RCD6_HUMAN | Calcium/calmodulin-dependent protei... | CAMK4 | 88 | Annotation score: |
Sequence cautioni
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_040604 | 150 | E → G in a lung adenocarcinoma sample; somatic mutation. 1 Publication | 1 | |
Natural variantiVAR_040605 | 178 | D → N1 PublicationCorresponds to variant dbSNP:rs35548075EnsemblClinVar. | 1 | |
Natural variantiVAR_040606 | 465 | Q → R1 PublicationCorresponds to variant dbSNP:rs56360861EnsemblClinVar. | 1 | |
Natural variantiVAR_040607 | 469 | I → M in a lung large cell carcinoma sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs1239950009Ensembl. | 1 |
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 |
CCDSi | CCDS4103.1 |
PIRi | A53036 |
RefSeqi | NP_001310303.1, NM_001323374.1 NP_001310304.1, NM_001323375.1 NP_001735.1, NM_001744.5 |
Genome annotation databases
Ensembli | ENST00000282356.9; ENSP00000282356.4; ENSG00000152495.11 ENST00000512453.5; ENSP00000422634.1; ENSG00000152495.11 |
GeneIDi | 814 |
KEGGi | hsa:814 |
MANE-Selecti | ENST00000282356.9; ENSP00000282356.4; NM_001744.6; NP_001735.1 |
UCSCi | uc003kpf.4, human |
Similar proteinsi
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 |
CCDSi | CCDS4103.1 |
PIRi | A53036 |
RefSeqi | NP_001310303.1, NM_001323374.1 NP_001310304.1, NM_001323375.1 NP_001735.1, NM_001744.5 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
2W4O | X-ray | 2.17 | A | 15-340 | [»] | |
AlphaFoldDBi | Q16566 | |||||
SMRi | Q16566 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 107264, 26 interactors |
DIPi | DIP-41997N |
IntActi | Q16566, 30 interactors |
STRINGi | 9606.ENSP00000282356 |
Chemistry databases
BindingDBi | Q16566 |
ChEMBLi | CHEMBL2494 |
DrugBanki | DB07676, 3-({[(3S)-3,4-dihydroxybutyl]oxy}amino)-1H,2'H-2,3'-biindol-2'-one DB07664, K-00546 |
DrugCentrali | Q16566 |
PTM databases
GlyGeni | Q16566, 7 sites, 1 O-linked glycan (3 sites) |
iPTMneti | Q16566 |
MetOSitei | Q16566 |
PhosphoSitePlusi | Q16566 |
Genetic variation databases
BioMutai | CAMK4 |
DMDMi | 2499586 |
Proteomic databases
EPDi | Q16566 |
jPOSTi | Q16566 |
MassIVEi | Q16566 |
MaxQBi | Q16566 |
PaxDbi | Q16566 |
PeptideAtlasi | Q16566 |
PRIDEi | Q16566 |
ProteomicsDBi | 60921 |
Protocols and materials databases
Antibodypediai | 2084, 626 antibodies from 42 providers |
DNASUi | 814 |
Genome annotation databases
Ensembli | ENST00000282356.9; ENSP00000282356.4; ENSG00000152495.11 ENST00000512453.5; ENSP00000422634.1; ENSG00000152495.11 |
GeneIDi | 814 |
KEGGi | hsa:814 |
MANE-Selecti | ENST00000282356.9; ENSP00000282356.4; NM_001744.6; NP_001735.1 |
UCSCi | uc003kpf.4, human |
Organism-specific databases
CTDi | 814 |
DisGeNETi | 814 |
GeneCardsi | CAMK4 |
HGNCi | HGNC:1464, CAMK4 |
HPAi | ENSG00000152495, Group enriched (brain, lymphoid tissue) |
MIMi | 114080, gene |
neXtProti | NX_Q16566 |
OpenTargetsi | ENSG00000152495 |
PharmGKBi | PA26050 |
VEuPathDBi | HostDB:ENSG00000152495 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG0032, Eukaryota |
GeneTreei | ENSGT00940000160006 |
HOGENOMi | CLU_000288_63_0_1 |
InParanoidi | Q16566 |
OMAi | TKMVPEA |
OrthoDBi | 330091at2759 |
PhylomeDBi | Q16566 |
TreeFami | TF351230 |
Enzyme and pathway databases
BRENDAi | 2.7.11.17, 2681 |
PathwayCommonsi | Q16566 |
Reactomei | R-HSA-111932, CaMK IV-mediated phosphorylation of CREB R-HSA-2151201, Transcriptional activation of mitochondrial biogenesis R-HSA-442729, CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde R-HSA-9022535, Loss of phosphorylation of MECP2 at T308 R-HSA-9022692, Regulation of MECP2 expression and activity R-HSA-9617324, Negative regulation of NMDA receptor-mediated neuronal transmission |
SignaLinki | Q16566 |
SIGNORi | Q16566 |
Miscellaneous databases
BioGRID-ORCSi | 814, 5 hits in 1104 CRISPR screens |
ChiTaRSi | CAMK4, human |
EvolutionaryTracei | Q16566 |
GeneWikii | CAMK4 |
GenomeRNAii | 814 |
Pharosi | Q16566, Tbio |
PROi | PR:Q16566 |
RNActi | Q16566, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000152495, Expressed in caudate nucleus and 164 other tissues |
ExpressionAtlasi | Q16566, baseline and differential |
Genevisiblei | Q16566, HS |
Family and domain databases
InterProi | View protein in InterPro IPR011009, Kinase-like_dom_sf IPR000719, Prot_kinase_dom IPR017441, Protein_kinase_ATP_BS IPR008271, Ser/Thr_kinase_AS |
Pfami | View protein in Pfam PF00069, Pkinase, 1 hit |
SMARTi | View protein in SMART SM00220, S_TKc, 1 hit |
SUPFAMi | SSF56112, SSF56112, 1 hit |
PROSITEi | View protein in PROSITE PS00107, PROTEIN_KINASE_ATP, 1 hit PS50011, PROTEIN_KINASE_DOM, 1 hit PS00108, PROTEIN_KINASE_ST, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | KCC4_HUMAN | |
Accessioni | Q16566Primary (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: | May 25, 2022 | |
This is version 197 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any 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, Reference proteomeDocuments
- Human and mouse protein kinases
Human and mouse protein kinases: classification and index - Human chromosome 5
Human chromosome 5: entries, gene names and cross-references to MIM - Human entries with genetic variants
List of human entries with genetic variants - Human variants curated from literature reports
Index of human variants curated from literature reports - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references - SIMILARITY comments
Index of protein domains and families