Calcium/calmodulin-dependent protein kinase type 1

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Q14012 (KCC1A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified December 14, 2011. Version 122. History...

Clusters with 100%, 90%, 50% identity |

Documents (6) |

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Names·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents Customize order

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	370 AA.
Sequence status	Complete.
Protein existence	Evidence 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 phopshorylating 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, SYN1/synapsin I and SYNII/synapsin II. 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
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 By similarity.
Post-translational modification	Phosphorylated by CaMKK1 and CaMKK2 on Thr-177. Ref.1 Ref.4 Ref.5 Ref.6 Ref.8 Ref.12
Sequence similarities	Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Cell cycle Differentiation Neurogenesis
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Calmodulin-binding Nucleotide-binding
Molecular function	Developmental protein Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Allosteric enzyme Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	cell cycle Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of dendritic spine development Inferred from mutant phenotype Ref.12. Source: UniProtKB positive regulation of muscle cell differentiation Inferred from mutant phenotype. Source: BHF-UCL positive regulation of neuron projection development Inferred from direct assay Ref.10. Source: UniProtKB 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 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. Source: ProtInc
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW calmodulin 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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 370

370

Calcium/calmodulin-dependent protein kinase type 1

PRO_0000086076

Regions

Domain

20 – 276

257

Protein kinase

Nucleotide binding

26 – 34

ATP By similarity

Region

276 – 316

Autoinhibitory domain By similarity

Region

296 – 317

Calmodulin-binding By similarity

Motif

315 – 321

Nuclear export signal By similarity

Sites

Active site

141

Proton acceptor By similarity

Binding site

ATP

Amino acid modifications

Modified residue

177

Phosphothreonine; by CaMKK1 and CaMKK2 Ref.1

Natural variations

Natural variant

217

P → S in a metastatic melanoma sample; somatic mutation. Ref.18

VAR_040596

Natural variant

361

E → K. Ref.18
Corresponds to variant rs56033923 [ dbSNP | Ensembl ].

VAR_040597

Experimental info

Mutagenesis

K → A: Catalytically inactive form; prevents CDK4 activation. Ref.1 Ref.9

Mutagenesis

177

T → A: Loss of activation by CaMKK1. Ref.1

Mutagenesis

177

T → D: Partial activation in absence of CaMKK1. Ref.1

Sequences

Sequence

Length

Mass (Da)

Tools

Q14012 [UniParc].

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

FASTA

370

41,337

        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' referencesShow '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: 7641687] [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: 15489334] [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: 12665801] [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: 9662074] [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: 11114197] [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: 11395482] [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: 12193581] [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: 14507913] [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: 14754892] [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: 17442826] [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: 17056143] [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: 18184567] [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: 20181577] [Abstract] Cited for: FUNCTION IN AXON ELONGATION.
[14]	"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: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[15]	"Structure and regulation of calcium/calmodulin-dependent protein kinases." Soderling T.R., Stull J.T. Chem. Rev. 101:2341-2352(2001) [PubMed: 11749376] [Abstract] Cited for: REVIEW.
[16]	"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: 18817731] [Abstract] Cited for: REVIEW ON FUNCTION IN NEURONAL PLASTICITY.
[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: 21301225] [Abstract] Cited for: REVIEW ON INVOLVEMENT IN CELL CYCLE.
[18]	"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] 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.
IPI	IPI00028296.
PIR	S57347.
RefSeq	NP_003647.1. NM_003656.4.
UniGene	Hs.434875.
3D structure databases
ProteinModelPortal	Q14012.
SMR	Q14012. Positions 10-316.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-41906N.
STRING	Q14012.
PTM databases
PhosphoSite	Q14012.
Polymorphism databases
DMDM	3122301.
Proteomic databases
PeptideAtlas	Q14012.
PRIDE	Q14012.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000256460; ENSP00000256460; ENSG00000134072.
GeneID	8536.
KEGG	hsa:8536.
NMPDR	fig\|9606.3.peg.22087.
UCSC	uc003bst.1. human.
Organism-specific databases
CTD	8536.
GeneCards	GC03M009774.
H-InvDB	HIX0200512.
HGNC	HGNC:1459. CAMK1.
HPA	CAB031904.
MIM	604998. gene.
neXtProt	NX_Q14012.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG07976.
GeneTree	ENSGT00600000084207.
HOGENOM	HBG755340.
HOVERGEN	HBG108055.
InParanoid	Q14012.
OMA	RHNNIVQ.
OrthoDB	EOG46Q6SS.
PhylomeDB	Q14012.
Enzyme and pathway databases
BRENDA	2.7.11.17. 2681.
Gene expression databases
ArrayExpress	Q14012.
Bgee	Q14012.
CleanEx	HS_CAMK1.
Genevestigator	Q14012.
GermOnline	ENSG00000134072. Homo sapiens.
Family and domain databases
InterPro	IPR020636. Ca/CaM-dep_Ca-dep_prot_Kinase. IPR011009. 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]
KO	K08794.
PANTHER	PTHR24347. PTHR24347. 1 hit.
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	31972.
SOURCE	Search...

Entry information

Entry name

KCC1A_HUMAN

Accession

Primary (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:	December 14, 2011
This is version 122 of the entry and version 1 of the sequence. [Complete history]

Entry status

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.

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

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List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

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

SIMILARITY comments

Index of protein domains and families

Names·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents

Preferred order of sections

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations

Experimental info

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Polymorphism databases

Proteomic databases

Protocols and materials databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other

Entry information

Relevant documents