Calcium/calmodulin-dependent protein kinase type IV

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Reviewed, UniProtKB/Swiss-Prot Q16566 (KCC4_HUMAN)

Last modified November 3, 2009. Version 94. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    Calcium/calmodulin-dependent protein kinase type IV
      Short name=CaMK IV
    EC=2.7.11.17
Alternative name(s):
    CAM kinase-GR

Gene names

Name:

CAMK4

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	473 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade. May be involved in transcriptional regulation. May be involved in regulation of microtubule dynamics. In vitro, phosphorylates CREB1, CREBBP, PRM2, MEF2A, MEF2D and STMN1/OP18. May be involved in spermatogenesis. May play a role in the consolidation/retention of hippocampus-dependent long-term memory By similarity.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Activated by Ca²⁺/calmodulin. Binding of calmodulin may releave intrasteric autoinhibition. Must be phosphorylated to be maximally active. Phosphorylated by CAMKK1 or CAMKK2. Autophosphorylation of the N-terminus is required for full activation. In part, activity is independent on Ca²⁺/calmodulin and autophosphorylation of Ser-336 allows to switch to a Ca²⁺/calmodulin-independent state By similarity. Probably inactivated by serine/threonine protein phosphatase 2A.
Subunit structure	Monomer By similarity. Interacts with serine/threonine protein phosphatase 2A catalytic subunit, PPP2CA or PPP2CB. The interaction with PP2CA or PP2CB is mutually exclusive with binding to Ca²⁺/calmodulin.
Subcellular location	Cytoplasm By similarity. Nucleus By similarity. Note: Substantial localization in certain neuronal nuclei. In spermatids associated with chromatin and nuclear matrix By similarity.
Tissue specificity	Expressed in epithelial ovarian cancer tissue. Ref.8
Post-translational modification	Autophosphorylated and phosphorylated by CAMKK1 and CAMKK2 By similarity. Dephosphorylated by serine/threonine protein phosphatase 2A, probably on Thr-200.
Sequence similarities	Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily. Contains 1 protein kinase domain.

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Ontologies

Keywords
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Calcium Calmodulin-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	protein amino acid phosphorylation Ref.1 Traceable author statement. Source: ProtInc signal transduction Ref.1 Traceable author statement. Source: ProtInc
Cellular component	cytosol Inferred from Experiment. Source: Reactome nucleolus Inferred from direct assay. Source: HPA nucleoplasm Ref.5 Inferred from Experiment. Source: Reactome
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW calcium ion binding Inferred from electronic annotation. Source: UniProtKB-KW calmodulin binding Inferred from electronic annotation. Source: UniProtKB-KW calmodulin-dependent protein kinase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 473

473

Calcium/calmodulin-dependent protein kinase type IV

PRO_0000086106

Regions

Domain

46 – 300

255

Protein kinase

Nucleotide binding

52 – 60

ATP By similarity

Region

301 – 340

Autoinhibitory domain

Region

322 – 341

Calmodulin-binding Potential

Sites

Active site

164

Proton acceptor By similarity

Binding site

ATP By similarity

Amino acid modifications

Modified residue

Phosphoserine; by autocatalysis Ref.5

Modified residue

Phosphoserine; by autocatalysis Ref.5

Modified residue

190

N6-acetyllysine Ref.12

Modified residue

200

Phosphothreonine Ref.5 Ref.9

Modified residue

336

Phosphoserine; by autocatalysis

Modified residue

341

Phosphoserine Ref.10

Modified residue

360

Phosphoserine Ref.10

Natural variations

Natural variant

150

E → G in a lung adenocarcinoma sample; somatic mutation. Ref.13

VAR_040604

Natural variant

178

D → N: dbSNP rs35548075. Ref.13

VAR_040605

Natural variant

465

Q → R

VAR_040606

Natural variant

469

I → M in a lung large cell carcinoma sample; somatic mutation. Ref.13

VAR_040607

Experimental info

Mutagenesis

S → A: Loss of activity. Ref.5 Ref.9

Mutagenesis

S → A: Loss of activity. Ref.5 Ref.9

Mutagenesis

320 – 321

FN → DD: Loss of interaction with PPP2CA/PPP2CB. Ref.9

Secondary structure

473

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

Q16566-1 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: EFEE51E5612326DC
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FASTA

473

51,926

        10         20         30         40         50         60 
MLKVTVPSCS ASSCSSVTAS AAPGTASLVP DYWIDGSNRD ALSDFFEVES ELGRGATSIV 

        70         80         90        100        110        120 
YRCKQKGTQK PYALKVLKKT VDKKIVRTEI GVLLRLSHPN IIKLKEIFET PTEISLVLEL 

       130        140        150        160        170        180 
VTGGELFDRI VEKGYYSERD AADAVKQILE AVAYLHENGI VHRDLKPENL LYATPAPDAP 

       190        200        210        220        230        240 
LKIADFGLSK IVEHQVLMKT VCGTPGYCAP EILRGCAYGP EVDMWSVGII TYILLCGFEP 

       250        260        270        280        290        300 
FYDERGDQFM FRRILNCEYY FISPWWDEVS LNAKDLVRKL IVLDPKKRLT TFQALQHPWV 

       310        320        330        340        350        360 
TGKAANFVHM DTAQKKLQEF NARRKLKAAV KAVVASSRLG SASSSHGSIQ ESHKASRDPS 

       370        380        390        400        410        420 
PIQDGNEDMK AIPEGEKIQG DGAQAAVKGA QAELMKVQAL EKVKGADINA EEAPKMVPKA 

       430        440        450        460        470 
VEDGIKVADL ELEEGLAEEK LKTVEEAAAP REGQGSSAVG FEVPQQDVIL PEY

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"cDNA cloning and expression of human calmodulin-dependent protein kinase IV." Kitani T., Okuno S., Fujisawa H. J. Biochem. 115:637-640(1994) [PubMed: 8089075] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"The cDNA sequence and characterization of the Ca2+/calmodulin-dependent protein kinase-Gr from human brain and thymus." Bland M.M., Monroe R.S., Ohmstede C.A. Gene 142:191-197(1994) [PubMed: 8194751] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Cerebellum and Thymus.
[3]	"A Ca2+/calmodulin-dependent protein kinase, CaM kinase-Gr, expressed after transformation of primary human B lymphocytes by Epstein-Barr virus (EBV) is induced by the EBV oncogene LMP1." Mosialos G., Hanissian S.H., Jawahar S., Vara L., Kieff E., Chatila T.A. J. Virol. 68:1697-1705(1994) [PubMed: 8107230] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Blood.
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain and Lung.
[5]	"A unique phosphorylation-dependent mechanism for the activation of Ca2+/calmodulin-dependent protein kinase type IV/GR." Chatila T., Anderson K.A., Ho N., Means A.R. J. Biol. Chem. 271:21542-21548(1996) [PubMed: 8702940] [Abstract] Cited for: ENZYME REGULATION, PHOSPHORYLATION AT SER-12; SER-13 AND THR-200, MUTAGENESIS OF SER-12 AND SER-13.
[6]	"Regulation of microtubule dynamics by Ca2+/calmodulin-dependent kinase IV/Gr-dependent phosphorylation of oncoprotein 18." Melander Gradin H., Marklund U., Larsson N., Chatila T.A., Gullberg M. Mol. Cell. Biol. 17:3459-3467(1997) [PubMed: 9154845] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF STMN1.
[7]	"Ca(2+)-dependent gene expression mediated by MEF2 transcription factors." Blaeser F., Ho N., Prywes R., Chatila T.A. J. Biol. Chem. 275:197-209(2000) [PubMed: 10617605] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF MEF2A AND MEF2D.
[8]	"Ca(2+)/calmodulin-dependent protein kinase IV expression in epithelial ovarian cancer." Takai N., Miyazaki T., Nishida M., Nasu K., Miyakawa I. Cancer Lett. 183:185-193(2002) [PubMed: 12065094] [Abstract] Cited for: TISSUE SPECIFICITY.
[9]	"Regulation and function of the calcium/calmodulin-dependent protein kinase IV/protein serine/threonine phosphatase 2A signaling complex." Anderson K.A., Noeldner P.K., Reece K., Wadzinski B.E., Means A.R. J. Biol. Chem. 279:31708-31716(2004) [PubMed: 15143065] [Abstract] Cited for: ENZYME REGULATION, INTERACTION WITH SERINE/THREONINE PROTEIN PHOSPHATASE 2A, PHOSPHORYLATION AT THR-200, MUTAGENESIS OF 320-PHE-ASN-321.
[10]	"Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry." Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R., Keri G., Wehland J., Daub H. Mol. Cell. Proteomics 6:537-547(2007) [PubMed: 17192257] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-341 AND SER-360, MASS SPECTROMETRY.
[11]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[12]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed: 19608861] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-190, MASS SPECTROMETRY.
[13]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] GLY-150; ASN-178; ARG-465 AND MET-469.
+	Additional computationally mapped references.

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Cross-references

Sequence databases

D30742 mRNA. Translation: BAA06403.1.
L17000 mRNA. Translation: AAA35639.1.
L24959 mRNA. Translation: AAA18251.1.
BC016695 mRNA. Translation: AAH16695.2. Different initiation.
BC025687 mRNA. Translation: AAH25687.1.

IPI

IPI00430411.

PIR

A53036.

RefSeq

NP_001735.1.

UniGene

Hs.591269

3D structure databases

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2W4O	X-ray	2.17	A	15-340	[»]

ModBase

Search...

Protein-protein interaction databases

STRING

Q16566.

PTM databases

PhosphoSite

Q16566.

Proteomic databases

PeptideAtlas

Q16566.

PRIDE

Q16566.

Genome annotation databases

Ensembl

ENST00000282356; ENSP00000282356; ENSG00000152495; Homo sapiens. [Genome view]

GeneID

814.

KEGG

hsa:814.

UCSC

uc003kpf.1. human.

Organism-specific databases

CTD

814.

GeneCards

GC05P110587.

H-InvDB

HIX0005080.

HGNC

HGNC:1464. CAMK4.

HPA

CAB004347.
HPA011753.
HPA017206.

MIM

114080. gene.

PharmGKB

PA26050.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

Q16566.

HOVERGEN

Q16566.

OMA

VHEDEPP.

Enzyme and pathway databases

BRENDA

2.7.11.17. 247.

Pathway_Interaction_DB

nfat_3pathway. Role of Calcineurin-dependent NFAT signaling in lymphocytes.
hdac_classii_pathway. Signaling events mediated by HDAC Class II.
pi3kplctrkpathway. Trk receptor signaling mediated by PI3K and PLC-gamma.

Reactome

REACT_11061. Signalling by NGF.
REACT_15295. Opioid Signalling.

Gene expression databases

ArrayExpress

Q16566.

Bgee

Q16566.

CleanEx

HS_CAMK4.

Genevestigator

Q16566.

GermOnline

ENSG00000152495. Homo sapiens.

Family and domain databases

InterPro

IPR015733. Ca/calmodulin-dep_kinase_4.
IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_pkinase-rel.
IPR008271. Ser_thr_pkin_AS.
IPR002290. Ser_thr_pkinase.
[Graphical view]

PANTHER

PTHR22982:SF33. CaMKIV. 1 hit.

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

ProDom

PD000001. Prot_kinase. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00220. S_TKc. 1 hit.
[Graphical view]

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

3300.

PMAP-CutDB

Q16566.

SOURCE

Search...

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Entry information

Entry name

KCC4_HUMAN

Accession

Primary (citable) accession number: Q16566

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 1, 1996
Last modified:	November 3, 2009
This is version 94 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.

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