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Q14012 (KCC1A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 146. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Calcium/calmodulin-dependent protein kinase type 1

EC=2.7.11.17
Alternative name(s):
CaM kinase I
Short name=CaM-KI
CaM kinase I alpha
Short name=CaMKI-alpha
Gene names
Name:CAMK1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length370 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, regulates transcription activators activity, cell cycle, hormone production, cell differentiation, actin filament organization and neurite outgrowth. Recognizes the substrate consensus sequence [MVLIF]-x-R-x(2)-[ST]-x(3)-[MVLIF]. Regulates axonal extension and growth cone motility in hippocampal and cerebellar nerve cells. Upon NMDA receptor-mediated Ca2+ elevation, promotes dendritic growth in hippocampal neurons and is essential in synapses for full long-term potentiation (LTP) and ERK2-dependent translational activation. Downstream of NMDA receptors, promotes the formation of spines and synapses in hippocampal neurons by phosphorylating ARHGEF7/BETAPIX on 'Ser-694', which results in the enhancement of ARHGEF7 activity and activation of RAC1. Promotes neuronal differentiation and neurite outgrowth by activation and phosphorylation of MARK2 on 'Ser-91', 'Ser-92', 'Ser-93' and 'Ser-294'. Promotes nuclear export of HDAC5 and binding to 14-3-3 by phosphorylation of 'Ser-259' and 'Ser-498' in the regulation of muscle cell differentiation. Regulates NUMB-mediated endocytosis by phosphorylation of NUMB on 'Ser-276' and 'Ser-295'. Involved in the regulation of basal and estrogen-stimulated migration of medulloblastoma cells through ARHGEF7/BETAPIX phosphorylation By similarity. Is required for proper activation of cyclin-D1/CDK4 complex during G1 progression in diploid fibroblasts. Plays a role in K+ and ANG2-mediated regulation of the aldosterone synthase (CYP11B2) to produce aldosterone in the adrenal cortex. Phosphorylates EIF4G3/eIF4GII. In vitro phosphorylates CREB1, ATF1, CFTR, MYL9 and SYN1/synapsin I. Ref.5 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 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-177 within the activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-177 results in several fold increase in total activity. Unlike CaMK4, is unable to exhibit autonomous activity after Ca2+/calmodulin activation. Ref.1 Ref.20

Subunit structure

Monomer. Interacts with XPO1 By similarity. Interacts with MARK2, ARHGEF7/BETAPIX and GIT1. Ref.10 Ref.12

Subcellular location

Cytoplasm By similarity. Nucleus By similarity. Note: Predominantly cytoplasmic By similarity.

Tissue specificity

Widely expressed. Expressed in cells of the zona glomerulosa of the adrenal cortex. Ref.7 Ref.11

Domain

The autoinhibitory domain overlaps with the calmodulin binding region and interacts in the inactive folded state with the catalytic domain as a pseudosubstrate. Ref.20

Post-translational modification

Phosphorylated by CaMKK1 and CaMKK2 on Thr-177. Ref.1 Ref.4 Ref.6

Polybiquitinated by the E3 ubiquitin-protein ligase complex SCF(FBXL12), leading to proteasomal degradation.

Sequence similarities

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

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processCell cycle
Differentiation
Neurogenesis
   Cellular componentCytoplasm
Nucleus
   Coding sequence diversityPolymorphism
   LigandATP-binding
Calmodulin-binding
Nucleotide-binding
   Molecular functionDevelopmental protein
Kinase
Serine/threonine-protein kinase
Transferase
   PTMIsopeptide bond
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Allosteric enzyme
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processcell cycle

Inferred from electronic annotation. Source: UniProtKB-KW

nucleocytoplasmic transport

Inferred from electronic annotation. Source: Ensembl

positive regulation of dendritic spine development

Inferred from mutant phenotype Ref.12. Source: UniProtKB

positive regulation of muscle cell differentiation

Inferred from mutant phenotype PubMed 11081517. Source: BHF-UCL

positive regulation of neuron projection development

Inferred from direct assay Ref.10. Source: UniProtKB

positive regulation of protein export from nucleus

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein serine/threonine kinase activity

Inferred from direct assay Ref.10. Source: UniProtKB

positive regulation of synapse structural plasticity

Inferred from mutant phenotype Ref.12. Source: UniProtKB

protein phosphorylation

Inferred from direct assay Ref.5. Source: UniProtKB

regulation of muscle cell differentiation

Inferred from direct assay Ref.5. Source: UniProtKB

regulation of protein binding

Inferred from direct assay Ref.5. Source: UniProtKB

regulation of protein localization

Inferred from direct assay Ref.5. Source: UniProtKB

signal transduction

Traceable author statement Ref.1PubMed 9395448. Source: ProtInc

   Cellular_componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

calmodulin-dependent protein kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 370370Calcium/calmodulin-dependent protein kinase type 1
PRO_0000086076

Regions

Domain20 – 276257Protein kinase
Nucleotide binding26 – 349ATP
Region276 – 31641Autoinhibitory domain
Region296 – 31722Calmodulin-binding By similarity
Motif315 – 3217Nuclear export signal By similarity

Sites

Active site1411Proton acceptor By similarity
Binding site491ATP

Amino acid modifications

Modified residue1771Phosphothreonine; by CaMKK1 and CaMKK2 Ref.1
Cross-link59Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Probable

Natural variations

Natural variant2171P → S in a metastatic melanoma sample; somatic mutation. Ref.21
VAR_040596
Natural variant3611E → K. Ref.21
Corresponds to variant rs56033923 [ dbSNP | Ensembl ].
VAR_040597

Experimental info

Mutagenesis491K → A: Catalytically inactive form; prevents CDK4 activation. Ref.1 Ref.9
Mutagenesis1771T → A: Loss of activation by CaMKK1. Ref.1
Mutagenesis1771T → D: Partial activation in absence of CaMKK1. Ref.1

Secondary structure

.................................................... 370
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q14012 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 57FA20ECE00FA76C

FASTA37041,337
        10         20         30         40         50         60 
MLGAVEGPRW KQAEDIRDIY DFRDVLGTGA FSEVILAEDK RTQKLVAIKC IAKEALEGKE 

        70         80         90        100        110        120 
GSMENEIAVL HKIKHPNIVA LDDIYESGGH LYLIMQLVSG GELFDRIVEK GFYTERDASR 

       130        140        150        160        170        180 
LIFQVLDAVK YLHDLGIVHR DLKPENLLYY SLDEDSKIMI SDFGLSKMED PGSVLSTACG 

       190        200        210        220        230        240 
TPGYVAPEVL AQKPYSKAVD CWSIGVIAYI LLCGYPPFYD ENDAKLFEQI LKAEYEFDSP 

       250        260        270        280        290        300 
YWDDISDSAK DFIRHLMEKD PEKRFTCEQA LQHPWIAGDT ALDKNIHQSV SEQIKKNFAK 

       310        320        330        340        350        360 
SKWKQAFNAT AVVRHMRKLQ LGTSQEGQGQ TASHGELLTP VAGGPAAGCC CRDCCVEPGT 

       370 
ELSPTLPHQL 

« Hide

References

« Hide 'large scale' references
[1]"Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase."
Haribabu B., Hook S.S., Selbert M.A., Goldstein E.G., Tomhave E.D., Edelman A.M., Snyderman R., Means A.R.
EMBO J. 14:3679-3686(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PHOSPHORYLATION AT THR-177, MUTAGENESIS OF LYS-49 AND THR-177, ENZYME REGULATION.
[2]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]"Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides."
Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., Vandekerckhove J.
Nat. Biotechnol. 21:566-569(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 1-9.
Tissue: Platelet.
[4]"Cloning, expression and chromosomal localization of human Ca2+/calmodulin-dependent protein kinase kinase."
Hsu L.-S., Tsou A.-P., Chi C.-W., Lee C.-H., Chen J.-Y.
J. Biomed. Sci. 5:141-149(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION BY CAMKK1.
[5]"Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5."
McKinsey T.A., Zhang C.-L., Olson E.N.
Proc. Natl. Acad. Sci. U.S.A. 97:14400-14405(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF HDAC5.
[6]"Human Ca2+/calmodulin-dependent protein kinase kinase beta gene encodes multiple isoforms that display distinct kinase activity."
Hsu L.-S., Chen G.-D., Lee L.-S., Chi C.-W., Cheng J.-F., Chen J.-Y.
J. Biol. Chem. 276:31113-31123(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION BY CAMKK2.
[7]"Calmodulin-dependent kinase I regulates adrenal cell expression of aldosterone synthase."
Condon J.C., Pezzi V., Drummond B.M., Yin S., Rainey W.E.
Endocrinology 143:3651-3657(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, TISSUE SPECIFICITY.
[8]"Phosphorylation screening identifies translational initiation factor 4GII as an intracellular target of Ca(2+)/calmodulin-dependent protein kinase I."
Qin H., Raught B., Sonenberg N., Goldstein E.G., Edelman A.M.
J. Biol. Chem. 278:48570-48579(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF EIF4G3.
[9]"Regulation of cyclin D1/Cdk4 complexes by calcium/calmodulin-dependent protein kinase I."
Kahl C.R., Means A.R.
J. Biol. Chem. 279:15411-15419(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CYCLIN-D1/CDK4 COMPLEX, MUTAGENESIS OF LYS-49.
[10]"A calcium- and calmodulin-dependent kinase Ialpha/microtubule affinity regulating kinase 2 signaling cascade mediates calcium-dependent neurite outgrowth."
Uboha N.V., Flajolet M., Nairn A.C., Picciotto M.R.
J. Neurosci. 27:4413-4423(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH MARK2.
[11]"Spatiotemporal expression of four isoforms of Ca2+/calmodulin-dependent protein kinase I in brain and its possible roles in hippocampal dendritic growth."
Kamata A., Sakagami H., Tokumitsu H., Owada Y., Fukunaga K., Kondo H.
Neurosci. Res. 57:86-97(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN HIPPOCAMPAL DENDRITITE GROWTH, TISSUE SPECIFICITY.
[12]"Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/betaPIX signaling complex."
Saneyoshi T., Wayman G., Fortin D., Davare M., Hoshi N., Nozaki N., Natsume T., Soderling T.R.
Neuron 57:94-107(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF ARHGEF7/BETAPIX, INTERACTION WITH ARHGEF7/BETAPIX AND GIT1.
[13]"CaMKK-CaMKI signaling pathways differentially control axon and dendrite elongation in cortical neurons."
Neal A.P., Molina-Campos E., Marrero-Rosado B., Bradford A.B., Fox S.M., Kovalova N., Hannon H.E.
J. Neurosci. 30:2807-2809(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN AXON ELONGATION.
[14]"Structure and regulation of calcium/calmodulin-dependent protein kinases."
Soderling T.R., Stull J.T.
Chem. Rev. 101:2341-2352(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[15]"Calmodulin-kinases: modulators of neuronal development and plasticity."
Wayman G.A., Lee Y.S., Tokumitsu H., Silva A.J., Silva A., Soderling T.R.
Neuron 59:914-931(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION IN NEURONAL PLASTICITY.
[16]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[17]"Controlling the cell cycle: the role of calcium/calmodulin-stimulated protein kinases I and II."
Skelding K.A., Rostas J.A., Verrills N.M.
Cell Cycle 10:631-639(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON INVOLVEMENT IN CELL CYCLE.
[18]"N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB."
Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[19]"Fbxl12 triggers G1 arrest by mediating degradation of calmodulin kinase I."
Mallampalli R.K., Kaercher L., Snavely C., Pulijala R., Chen B.B., Coon T., Zhao J., Agassandian M.
Cell. Signal. 25:2047-2059(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION AT LYS-59.
[20]"Crystal structures of human CaMKIalpha reveal insights into the regulation mechanism of CaMKI."
Zha M., Zhong C., Ou Y., Han L., Wang J., Ding J.
PLoS ONE 7:E44828-E44828(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-315 IN COMPLEXES WITH ATP, DOMAIN, ENZYME REGULATION.
[21]"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. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] SER-217 AND LYS-361.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
L41816 mRNA. Translation: AAA99458.1.
BC106754 mRNA. Translation: AAI06755.1.
BC106755 mRNA. Translation: AAI06756.1.
PIRS57347.
RefSeqNP_003647.1. NM_003656.4.
UniGeneHs.434875.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4FG7X-ray2.70A1-293[»]
4FG8X-ray2.20A/B1-315[»]
4FG9X-ray2.40A/B1-320[»]
4FGBX-ray2.60A1-320[»]
ProteinModelPortalQ14012.
SMRQ14012. Positions 10-299.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid114106. 96 interactions.
DIPDIP-41906N.
IntActQ14012. 1 interaction.
MINTMINT-201810.
STRING9606.ENSP00000256460.

Chemistry

BindingDBQ14012.
ChEMBLCHEMBL2493.
GuidetoPHARMACOLOGY1952.

PTM databases

PhosphoSiteQ14012.

Polymorphism databases

DMDM3122301.

Proteomic databases

PaxDbQ14012.
PeptideAtlasQ14012.
PRIDEQ14012.

Protocols and materials databases

DNASU8536.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000256460; ENSP00000256460; ENSG00000134072.
GeneID8536.
KEGGhsa:8536.
UCSCuc003bst.3. human.

Organism-specific databases

CTD8536.
GeneCardsGC03M009774.
HGNCHGNC:1459. CAMK1.
HPACAB031904.
HPA051409.
MIM604998. gene.
neXtProtNX_Q14012.
PharmGKBPA26048.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000233016.
HOVERGENHBG108055.
InParanoidQ14012.
KOK08794.
OMAARMYLMA.
OrthoDBEOG7WHH9K.
PhylomeDBQ14012.
TreeFamTF314166.

Enzyme and pathway databases

BRENDA2.7.11.17. 2681.
SignaLinkQ14012.

Gene expression databases

ArrayExpressQ14012.
BgeeQ14012.
CleanExHS_CAMK1.
GenevestigatorQ14012.

Family and domain databases

InterProIPR020636. Ca/CaM-dep_Ca-dep_prot_Kinase.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PANTHERPTHR24347. PTHR24347. 1 hit.
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiCAMK1.
GenomeRNAi8536.
NextBio31972.
PROQ14012.
SOURCESearch...

Entry information

Entry nameKCC1A_HUMAN
AccessionPrimary (citable) accession number: Q14012
Secondary accession number(s): Q3KPF6
Entry history
Integrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: November 1, 1996
Last modified: April 16, 2014
This is version 146 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 3

Human chromosome 3: entries, gene names and cross-references to MIM