Q14012 (KCC1A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

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) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › 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 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.18
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.18
Post-translational modification	Phosphorylated by CaMKK1 and CaMKK2 on Thr-177. Ref.1 Ref.4 Ref.6
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	3D-structure Allosteric enzyme Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	cell cycle Inferred from electronic annotation. Source: UniProtKB-KW nucleocytoplasmic transport Inferred from electronic annotation. Source: Compara 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: Compara 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 Ref.1PubMed 9395448. 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-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

9

ATP

Region

276 – 316

41

Autoinhibitory domain

Region

296 – 317

22

Calmodulin-binding By similarity

Motif

315 – 321

7

Nuclear export signal By similarity

Sites

Active site

141

1

Proton acceptor By similarity

Binding site

49

1

ATP

Amino acid modifications

Modified residue

177

1

Phosphothreonine; by CaMKK1 and CaMKK2 Ref.1

Natural variations

Natural variant

217

1

P → S in a metastatic melanoma sample; somatic mutation. Ref.19

VAR_040596

Natural variant

361

1

E → K. Ref.19
Corresponds to variant rs56033923 [ dbSNP | Ensembl ].

VAR_040597

Experimental info

Mutagenesis

49

1

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

Mutagenesis

177

1

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

Mutagenesis

177

1

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

Secondary structure

1

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370

Helix Strand Turn

Details...

Helix

16 – 18

3

Beta strand

20 – 29

10

Beta strand

32 – 39

8

Turn

40 – 42

3

Beta strand

45 – 52

8

Helix

66 – 70

5

Beta strand

81 – 86

6

Beta strand

88 – 95

8

Beta strand

100 – 102

3

Helix

103 – 109

7

Helix

115 – 134

20

Helix

144 – 146

3

Beta strand

147 – 152

6

Beta strand

158 – 160

3

Helix

166 – 168

3

Helix

171 – 179

9

Turn

182 – 184

3

Helix

187 – 190

4

Helix

198 – 213

16

Helix

223 – 232

10

Turn

239 – 244

6

Helix

247 – 256

10

Turn

261 – 263

3

Helix

267 – 272

6

Helix

274 – 277

4

Helix

287 – 297

11

Helix

301 – 311

11

Sequences

	Sequence		Length	Mass (Da)
	Q14012 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 57FA20ECE00FA76C	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

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] [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]	"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.
[19]	"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. , 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.

IPI

IPI00028296.

PIR

S57347.

RefSeq

NP_003647.1. NM_003656.4.

UniGene

Hs.434875.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
4FG7	X-ray	2.70	A	1-293	[»]
4FG8	X-ray	2.20	A/B	1-315	[»]
4FG9	X-ray	2.40	A/B	1-320	[»]
4FGB	X-ray	2.60	A	1-320	[»]

ProteinModelPortal

Q14012.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-41906N.

STRING

9606.ENSP00000256460.

PTM databases

PhosphoSite

Q14012.

Polymorphism databases

DMDM

3122301.

Proteomic databases

PaxDb

Q14012.

PeptideAtlas

Q14012.

PRIDE

Q14012.

Protocols and materials databases

DNASU

8536.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000256460; ENSP00000256460; ENSG00000134072.

GeneID

8536.

KEGG

hsa:8536.

UCSC

uc003bst.3. human.

Organism-specific databases

CTD

8536.

GeneCards

GC03M009774.

HGNC

HGNC:1459. CAMK1.

HPA

CAB031904.

MIM

604998. gene.

neXtProt

NX_Q14012.

PharmGKB

PA26048.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233016.

HOVERGEN

HBG108055.

InParanoid

Q14012.

KO

K08794.

OMA

ARMYLMA.

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.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

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

BindingDB

Q14012.

ChEMBL

CHEMBL2493.

GenomeRNAi

8536.

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:	May 1, 2013
This is version 136 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.