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P13234 (KCC4_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified November 16, 2011. Version 116. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
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to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Calcium/calmodulin-dependent protein kinase type IV
Short name=CaMK IV
EC=2.7.11.17
Alternative name(s):
CaM kinase-GR
Calspermin
Gene names
Name:Camk4
OrganismRattus norvegicus (Rat)
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length474 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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 consodilation. 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 osteolclasts and dendritic cells (DCs). Mediates DCs survival by linking TLR4 and the regulation of temporal expression of BCL2. Phosphrylates 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. Ref.8 Ref.10 Ref.13

Calspermin (isoform 2) is a heat-stable, acidic, calmodulin-binding protein. Ref.8 Ref.10 Ref.13

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

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 By similarity. Ref.9 Ref.11 Ref.12 Ref.14

Subunit structure

Monomer By similarity. Interacts with protein phosphatase 2A (PPP2CA/PPP2CB); the interaction is mutually exclusive with binding to Ca2+/calmodulin By similarity. Ref.9 Ref.17 Ref.18

Subcellular location

Cytoplasm. Nucleus. Note: Localized in hippocampal neuron nuclei By similarity. In spermatids, associated with chromatin and nuclear matrix By similarity. Ref.10 Ref.19

Tissue specificity

Isoform 1 is expressed in brain and isoform 2 is testis specific.

Domain

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.

Post-translational modification

Phosphorylated by CaMKK1 and CaMKK2 on Thr-196. Dephosphorylated by protein phosphatase 2A. Autophosphorylated on Ser-11 and Ser-12 By similarity. Ref.8 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17

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.

The N-terminus of calspermin is blocked.

Sequence similarities

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

Contains 1 protein kinase domain.

Sequence caution

The sequence AAB28372.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Alternative products

This entry describes 2 isoforms produced by alternative promoter usage and alternative splicing. [Align] [Select]
Isoform 1 (identifier: P13234-1)

Also known as: Calcium-calmodulin-dependent protein kinase type IV; Beta;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P13234-2)

Also known as: Calspermin; Testis-specific;

The sequence of this isoform differs from the canonical sequence as follows:
     1-305: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 474474Calcium/calmodulin-dependent protein kinase type IV
PRO_0000086108

Regions

Domain42 – 296255Protein kinase
Nucleotide binding48 – 569ATP By similarity
Region297 – 33640Autoinhibitory domain
Region302 – 31918PP2A-binding By similarity
Region318 – 33720Calmodulin-binding Potential
Compositional bias393 – 3997Poly-Glu
Compositional bias403 – 41311Poly-Glu

Sites

Active site1601Proton acceptor By similarity
Binding site711ATP By similarity

Amino acid modifications

Modified residue111Phosphoserine; by autocatalysis By similarity
Modified residue121Phosphoserine; by autocatalysis By similarity
Modified residue1861N6-acetyllysine By similarity
Modified residue1961Phosphothreonine; by CaMKK1 and CaMKK2 By similarity
Modified residue3321Phosphoserine; by autocatalysis Ref.14
Modified residue3371Phosphoserine By similarity
Modified residue3521Phosphoserine By similarity
Glycosylation531O-linked (GlcNAc) By similarity
Glycosylation541O-linked (GlcNAc) By similarity
Glycosylation1331O-linked (GlcNAc) By similarity
Glycosylation1851O-linked (GlcNAc) By similarity
Glycosylation3401O-linked (GlcNAc) By similarity
Glycosylation3411O-linked (GlcNAc) By similarity
Glycosylation3521O-linked (GlcNAc) By similarity

Natural variations

Alternative sequence1 – 305305Missing in isoform 2.
VSP_004789

Experimental info

Mutagenesis711K → M: Loss of kinase activity; confers cytoplasmic localization. Ref.19
Mutagenesis1961T → A: Loss of kinase activity; confers nuclear localization. Ref.12 Ref.19
Mutagenesis2071E → K: Loss of kinase activity; confers nuclear localization. Ref.19
Mutagenesis305 – 3084HMDT → DEDD: Increases Ca(2+)/calmodulin-independent activity. Ref.9
Mutagenesis316 – 3172FN → DD: Increases Ca(2+)/calmodulin-independent activity.
Mutagenesis3321S → A: No decrease in Ca(2+)/calmodulin-dependent activity after activation by CaMKKs. Ref.14
Sequence conflict142 – 1432KQ → NE in AAA40845. Ref.1
Sequence conflict3721M → I in AAA40845. Ref.1
Sequence conflict3721M → I in AAA40865. Ref.1
Sequence conflict3721M → I in AAA41867. Ref.6

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (Calcium-calmodulin-dependent protein kinase type IV) (Beta) [UniParc].

Last modified February 1, 2005. Version 3.
Checksum: E7B20E942419EB89

FASTA47453,151
        10         20         30         40         50         60 
MLKVTVPSCP SSPCSSVTSS TENLVPDYWI DGSKRDPLSD FFEVESELGR GATSIVYRCK 

        70         80         90        100        110        120 
QKGTQKPYAL KVLKKTVDKK IVRTEIGVLL RLSHPNIIKL KEIFETPTEI SLVLELVTGG 

       130        140        150        160        170        180 
ELFDRIVEKG YYSERDAADA VKQILEAVAY LHENGIVHRD LKPENLLYAT PAPDAPLKIA 

       190        200        210        220        230        240 
DFGLSKIVEH QVLMKTVCGT PGYCAPEILR GCAYGPEVDM WSVGIITYIL LCGFEPFYDE 

       250        260        270        280        290        300 
RGDQFMFRRI LNCEYYFISP WWDEVSLNAK DLVKKLIVLD PKKRLTTFQA LQHPWVTGKA 

       310        320        330        340        350        360 
ANFVHMDTAQ KKLQEFNARR KLKAAVKAVV ASSRLGSASS SHTNIQESNK ASSEAQPAQD 

       370        380        390        400        410        420 
GKDKTDPLEN KMQAGDHEAA KAAADETMKL QSEEVEEEEG VKEEEEEEEE EEETSRMVPQ 

       430        440        450        460        470 
EPEDRLETDD QEMKRNSEET LKSVEEEMDP KAEEEAAAVG LGVPPQQDAI LPEY

« Hide

Isoform 2 (Calspermin) (Testis-specific) [UniParc].

Checksum: 4E4EBE821D179CA2
Show »

FASTA16918,732

References

« Hide 'large scale' references
[1]"Relationship of genes encoding Ca2+/calmodulin-dependent protein kinase Gr and calspermin: a gene within a gene."
Ohmstede C.-A., Bland M.M., Merrill B.M., Sahyoun N.
Proc. Natl. Acad. Sci. U.S.A. 88:5784-5788(1991) [PubMed: 1648230] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 437-474, PARTIAL PROTEIN SEQUENCE, ALTERNATIVE SPLICING.
[2]"A novel Ca2+/calmodulin-dependent protein kinase and a male germ cell-specific calmodulin-binding protein are derived from the same gene."
Means A.R., Cruzalegui F., Lemagueresse B., Needleman D.S., Slaughter G.R., Ono T.
Mol. Cell. Biol. 11:3960-3971(1991) [PubMed: 1649385] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
[3]"Cloning and sequencing of a gene encoding the beta polypeptide of Ca2+/calmodulin-dependent protein kinase IV and its expression confined to the mature cerebellar granule cells."
Sakagami H., Kondo H.
Brain Res. Mol. Brain Res. 19:215-218(1993) [PubMed: 8412563] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]"Organization and analysis of the complete rat calmodulin-dependent protein kinase IV gene."
Sun Z., Means R.L., LeMagueresse B., Means A.R.
J. Biol. Chem. 270:29507-29514(1995) [PubMed: 7493991] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]"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] (ISOFORM 1).
Tissue: Testis.
[6]"Ca2+/calmodulin-dependent protein kinase enriched in cerebellar granule cells. Identification of a novel neuronal calmodulin-dependent protein kinase."
Ohmstede C.-A., Jenson K.F., Sahyoun N.
J. Biol. Chem. 264:5866-5875(1989) [PubMed: 2538431] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 250-474 (ISOFORM 1).
Strain: Sprague-Dawley.
Tissue: Brain.
[7]"Molecular cloning sequence and distribution of rat calspermin, a high affinity calmodulin-binding protein."
Ono T., Slaughter G.R., Cook R.G., Means A.R.
J. Biol. Chem. 264:2081-2087(1989) [PubMed: 2914893] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 306-474 (ISOFORM 2), PROTEIN SEQUENCE OF 335-361.
Strain: Sprague-Dawley.
[8]"CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases."
Sheng M., Thompson M.A., Greenberg M.E.
Science 252:1427-1430(1991) [PubMed: 1646483] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF CREB1.
[9]"Activation mechanisms for Ca2+/calmodulin-dependent protein kinase IV. Identification of a brain CaM-kinase IV kinase."
Tokumitsu H., Brickey D.A., Glod J., Hidaka H., Sikela J., Soderling T.R.
J. Biol. Chem. 269:28640-28647(1994) [PubMed: 7961813] [Abstract]
Cited for: ENZYME REGULATION, SUBUNIT, MUTAGENESIS OF 305-HIS--THR-308 AND 316-PHE-ASN-317.
[10]"Calcium/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression."
Matthews R.P., Guthrie C.R., Wailes L.M., Zhao X., Means A.R., McKnight G.S.
Mol. Cell. Biol. 14:6107-6116(1994) [PubMed: 8065343] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF CREB1, SUBCELLULAR LOCATION.
[11]"Full activation of brain calmodulin-dependent protein kinase IV requires phosphorylation of the amino-terminal serine-rich region by calmodulin-dependent protein kinase IV kinase."
Okuno S., Kitani T., Fujisawa H.
J. Biochem. 117:686-690(1995) [PubMed: 7592527] [Abstract]
Cited for: ENZYME REGULATION, PHOSPHORYLATION.
[12]"Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation."
Selbert M.A., Anderson K.A., Huang Q.H., Goldstein E.G., Means A.R., Edelman A.M.
J. Biol. Chem. 270:17616-17621(1995) [PubMed: 7615569] [Abstract]
Cited for: ENZYME REGULATION, PHOSPHORYLATION AT THR-196, MUTAGENESIS OF THR-196.
[13]"Regulation of activating transcription factor-1 and the cAMP response element-binding protein by Ca2+/calmodulin-dependent protein kinases type I, II, and IV."
Sun P., Lou L., Maurer R.A.
J. Biol. Chem. 271:3066-3073(1996) [PubMed: 8621702] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF ATF1 AND CREB1.
[14]"Inactivation of calmodulin-dependent protein kinase IV by autophosphorylation of serine 332 within the putative calmodulin-binding domain."
Watanabe S., Okuno S., Kitani T., Fujisawa H.
J. Biol. Chem. 271:6903-6910(1996) [PubMed: 8636117] [Abstract]
Cited for: ENZYME REGULATION, PHOSPHORYLATION AT SER-332, MUTAGENESIS OF SER-332.
[15]"Multiple Ca(2+)-calmodulin-dependent protein kinase kinases from rat brain. Purification, regulation by Ca(2+)-calmodulin, and partial amino acid sequence."
Edelman A.M., Mitchelhill K.I., Selbert M.A., Anderson K.A., Hook S.S., Stapleton D., Goldstein E.G., Means A.R., Kemp B.E.
J. Biol. Chem. 271:10806-10810(1996) [PubMed: 8631893] [Abstract]
Cited for: PHOSPHORYLATION BY CAMKK1 AND CAMKK2.
[16]"Components of a calmodulin-dependent protein kinase cascade. Molecular cloning, functional characterization and cellular localization of Ca2+/calmodulin-dependent protein kinase kinase beta."
Anderson K.A., Means R.L., Huang Q.-H., Kemp B.E., Goldstein E.G., Selbert M.A., Edelman A.M., Fremeau R.T., Means A.R.
J. Biol. Chem. 273:31880-31889(1998) [PubMed: 9822657] [Abstract]
Cited for: PHOSPHORYLATION BY CAMKK2.
[17]"A signaling complex of Ca2+-calmodulin-dependent protein kinase IV and protein phosphatase 2A."
Westphal R.S., Anderson K.A., Means A.R., Wadzinski B.E.
Science 280:1258-1261(1998) [PubMed: 9596578] [Abstract]
Cited for: INTERACTION WITH SERINE/THREONINE PROTEIN PHOSPHATASE 2A, DEPHOSPHORYLATION.
[18]"Substrate recognition by Ca2+/Calmodulin-dependent protein kinase kinase. Role of the arg-pro-rich insert domain."
Tokumitsu H., Takahashi N., Eto K., Yano S., Soderling T.R., Muramatsu M.-A.
J. Biol. Chem. 274:15803-15810(1999) [PubMed: 10336483] [Abstract]
Cited for: INTERACTION WITH CAMKK1.
[19]"Catalytic activity is required for calcium/calmodulin-dependent protein kinase IV to enter the nucleus."
Lemrow S.M., Anderson K.A., Joseph J.D., Ribar T.J., Noeldner P.K., Means A.R.
J. Biol. Chem. 279:11664-11671(2004) [PubMed: 14701808] [Abstract]
Cited for: SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-71; THR-196 AND GLU-207.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ		M63334 mRNA. Translation: AAA40865.1.
M74488 Genomic DNA. Translation: AAA40845.1.
M64757 mRNA. Translation: AAA40856.1.
M64757 mRNA. Translation: AAA40857.1.
S65840 mRNA. Translation: AAB28372.1. Different initiation.
BC128706 mRNA. Translation: AAI28707.1.
J04600 mRNA. Translation: AAA41867.1.
J04446 mRNA. Translation: AAA40990.1.
IPIIPI00230883.
IPI00231822.
PIRTVRTC4. A41103.
I52637.
RefSeqNP_036859.2. NM_012727.3.
UniGeneRn.11046.

3D structure databases

ProteinModelPortalP13234.
ModBaseSearch...

Protein-protein interaction databases

STRINGP13234.

PTM databases

PhosphoSiteP13234.

Proteomic databases

PRIDEP13234.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000027771; ENSRNOP00000027771; ENSRNOG00000020478.
ENSRNOT00000042172; ENSRNOP00000049484; ENSRNOG00000020478.
GeneID25050.
KEGGrno:25050.
UCSCM64757. rat.
NM_012727. rat.

Organism-specific databases

CTD814.
RGD2264. Camk4.

Phylogenomic databases

eggNOGroNOG13085.
HOVERGENHBG108055.
InParanoidP13234.
OMATVPSCSA.
OrthoDBEOG4PNXH1.
PhylomeDBP13234.

Enzyme and pathway databases

BRENDA2.7.11.17. 5301.

Gene expression databases

ArrayExpressP13234.
GenevestigatorP13234.
GermOnlineENSRNOG00000020478. Rattus norvegicus.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_kinase-like_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR002290. Ser/Thr_kinase_dom.
[Graphical view]
KOK05869.
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. Kinase_like. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio605240.

Entry information

Entry nameKCC4_RAT
AccessionPrimary (citable) accession number: P13234
Secondary accession number(s): A1A5L5, Q63892
Entry history
Integrated into UniProtKB/Swiss-Prot: January 1, 1990
Last sequence update: February 1, 2005
Last modified: November 16, 2011
This is version 116 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents