Q63450 (KCC1A_RAT) 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

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	374 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-516', 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 By similarity. Regulates NUMB-mediated endocytosis by phosphorylation of NUMB on 'Ser-275' and 'Ser-294'. 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.6 Ref.9 Ref.13 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19
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.10 Ref.11
Subunit structure	Monomer. Interacts with XPO1. Ref.14
Subcellular location	Cytoplasm. Nucleus. Note: Predominantly cytoplasmic. Ref.8 Ref.12 Ref.13 Ref.14
Tissue specificity	Widely expressed. Ref.8
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.21
Post-translational modification	Phosphorylated by CaMKK1 and CaMKK2 on Thr-177. Ref.10
Miscellaneous	Dendrite development is blocked in hippocampal neurons silencing CAKM1.
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 AAA19670.1 differs from that shown. Reason: Frameshift at positions 321 and 363.

Ontologies

Keywords
Biological process	Cell cycle Differentiation Neurogenesis
Cellular component	Cytoplasm Nucleus
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 sequence or structural similarity. Source: UniProtKB positive regulation of muscle cell differentiation Inferred from electronic annotation. Source: Compara positive regulation of neuron projection development Inferred from sequence or structural similarity. 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 sequence or structural similarity. Source: UniProtKB positive regulation of synapse structural plasticity Inferred from sequence or structural similarity. Source: UniProtKB regulation of muscle cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB regulation of protein binding Inferred from sequence or structural similarity. Source: UniProtKB regulation of protein localization Inferred from sequence or structural similarity. Source: UniProtKB signal transduction Inferred from electronic annotation. Source: Compara
Cellular_component	calcium- and calmodulin-dependent protein kinase complex Traceable author statement PubMed 11264466. Source: UniProtKB 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 direct assay PubMed 17939993. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 374

374

Calcium/calmodulin-dependent protein kinase type 1

PRO_0000086078

Regions

Domain

20 – 276

257

Protein kinase

Nucleotide binding

26 – 34

9

ATP By similarity

Region

276 – 316

41

Autoinhibitory domain

Region

296 – 317

22

Calmodulin-binding

Motif

263 – 264

2

Involved in nuclear import Probable

Motif

315 – 321

7

Nuclear export signal

Sites

Active site

141

1

Proton acceptor

Binding site

49

1

ATP By similarity

Amino acid modifications

Modified residue

177

1

Phosphothreonine; by CaMKK1 and CaMKK2

Experimental info

Mutagenesis

177

1

T → A: Loss of activation by CaMKK1 and CaMKK2. Ref.10

Mutagenesis

263 – 264

2

KR → AA: Partially excluded from the nucleus; when associated with 319-AQA-321.

Mutagenesis

319 – 321

3

LQL → AQA: Retention in the nucleus. Partially excluded from the nucleus; when associated with 263-AA-264. Ref.14

Sequence conflict

37

1

A → T AA sequence Ref.5

Sequence conflict

112

1

F → G in AAA19670. Ref.1

Sequence conflict

118

1

A → R in AAA19670. Ref.1

Sequence conflict

239

1

S → V AA sequence Ref.5

Sequence conflict

309

1

A → R in AAA19670. Ref.1

Secondary structure

1

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374

Helix Strand Turn

Details...

Helix

16 – 18

3

Beta strand

20 – 28

9

Helix

29 – 33

5

Beta strand

34 – 39

6

Turn

40 – 42

3

Beta strand

45 – 52

8

Helix

65 – 71

7

Beta strand

81 – 86

6

Beta strand

88 – 95

8

Helix

103 – 108

6

Helix

115 – 134

20

Helix

144 – 146

3

Beta strand

147 – 153

7

Beta strand

158 – 160

3

Helix

187 – 190

4

Helix

198 – 213

16

Helix

223 – 231

9

Turn

239 – 244

6

Helix

247 – 256

10

Helix

261 – 263

3

Helix

267 – 272

6

Turn

274 – 276

3

Beta strand

277 – 279

3

Helix

287 – 297

11

Helix

298 – 317

20

Sequences

	Sequence		Length	Mass (Da)
	Q63450 [UniParc]. Last modified July 15, 1998. Version 2. Checksum: 37889B3DEF033AB2	FASTA	374	41,638
	10 20 30 40 50 60 MPGAVEGPRW KQAEDIRDIY DFRDVLGTGA FSEVILAEDK RTQKLVAIKC IAKKALEGKE 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 TAGGPAAGCC CRDCCVEPGS 370 ELPPAPPPSS RAMD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Calcium/calmodulin-dependent protein kinase I. cDNA cloning and identification of autophosphorylation site." Picciotto M.R., Czernik A.J., Nairn A.C. J. Biol. Chem. 268:26512-26521(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	Erratum Picciotto M.R., Czernik A.J., Nairn A.C. J. Biol. Chem. 270:10358-10358(1995)
[3]	"Characterization of a rat cDNA clone encoding calcium/calmodulin-dependent protein kinase I." Cho F.S., Phillips K.S., Bogucki B., Weaver T.E. Biochim. Biophys. Acta 1224:156-160(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Sprague-Dawley. Tissue: Lung.
[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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Lung.
[5]	"Purification and characterization of Ca2+/calmodulin-dependent protein kinase V from rat cerebrum." Mochizuki H., Ito T., Hidaka H. J. Biol. Chem. 268:9143-9147(1993) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 12-37; 158-167; 233-241 AND 285-295.
[6]	"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] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF CREB1.
[7]	"Similar substrate recognition motifs for mammalian AMP-activated protein kinase, higher plant HMG-CoA reductase kinase-A, yeast SNF1, and mammalian calmodulin-dependent protein kinase I." Dale S., Wilson W.A., Edelman A.M., Hardie D.G. FEBS Lett. 361:191-195(1995) [PubMed] [Europe PMC] [Abstract] Cited for: SUBSTRATE RECOGNITION MOTIF.
[8]	"Immunochemical localization of calcium/calmodulin-dependent protein kinase I." Picciotto M.R., Zoli M., Bertuzzi G., Nairn A.C. Synapse 20:75-84(1995) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[9]	"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] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF ATF1 AND CREB1.
[10]	"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] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION, PHOSPHORYLATION BY CAMKK1 AND CAMKK2, MUTAGENESIS OF THR-177.
[11]	"Activation of a calcium-calmodulin-dependent protein kinase I cascade in PC12 cells." Aletta J.M., Selbert M.A., Nairn A.C., Edelman A.M. J. Biol. Chem. 271:20930-20934(1996) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION.
[12]	"Expression and subcellular localization of multifunctional calmodulin-dependent protein kinases-I, -II and -IV are altered in rat hippocampal CA1 neurons after induction of long-term potentiation." Ahmed B.Y., Yamaguchi F., Tsumura T., Gotoh T., Sugimoto K., Tai Y., Konishi R., Kobayashi R., Tokuda M. Neurosci. Lett. 290:149-153(2000) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[13]	"Characterization of Ca2+/calmodulin-dependent protein kinase I as a myosin II regulatory light chain kinase in vitro and in vivo." Suizu F., Fukuta Y., Ueda K., Iwasaki T., Tokumitsu H., Hosoya H. Biochem. J. 367:335-345(2002) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, FUNCTION IN PHOSPHORYLATION OF MYL9.
[14]	"Cytoplasmic localization of calcium/calmodulin-dependent protein kinase I-alpha depends on a nuclear export signal in its regulatory domain." Stedman D.R., Uboha N.V., Stedman T.T., Nairn A.C., Picciotto M.R. FEBS Lett. 566:275-280(2004) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, NUCLEAR EXPORT SIGNAL, MUTAGENESIS OF 319-LEU--LEU-321 AND 263-LYS-ARG-264, INTERACTION WITH XPO1.
[15]	"Regulation of axonal extension and growth cone motility by calmodulin-dependent protein kinase I." Wayman G.A., Kaech S., Grant W.F., Davare M., Impey S., Tokumitsu H., Nozaki N., Banker G., Soderling T.R. J. Neurosci. 24:3786-3794(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN AXONAL OUTGROWTH.
[16]	"Calmodulin-dependent kinase kinase/calmodulin kinase I activity gates extracellular-regulated kinase-dependent long-term potentiation." Schmitt J.M., Guire E.S., Saneyoshi T., Soderling T.R. J. Neurosci. 25:1281-1290(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN LONG-TERM POTENTIATION.
[17]	"Phosphorylation of Numb regulates its interaction with the clathrin-associated adaptor AP-2." Tokumitsu H., Hatano N., Yokokura S., Sueyoshi Y., Nozaki N., Kobayashi R. FEBS Lett. 580:5797-5801(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF NUMB.
[18]	"Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2." Wayman G.A., Impey S., Marks D., Saneyoshi T., Grant W.F., Derkach V., Soderling T.R. Neuron 50:897-909(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN DENDTRITIC GROWTH.
[19]	"Calmodulin-kinases regulate basal and estrogen stimulated medulloblastoma migration via Rac1." Davare M.A., Saneyoshi T., Soderling T.R. J. Neurooncol. 104:65-82(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN MEDULLOBLASTOMA CELLS MIGRATION.
[20]	"Structural basis for the autoinhibition of calcium/calmodulin-dependent protein kinase I." Goldberg J., Nairn A.C., Kuriyan J. Cell 84:875-887(1996) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS). Tissue: Brain.
[21]	"Structure of the complex of calmodulin with the target sequence of calmodulin-dependent protein kinase I: studies of the kinase activation mechanism." Clapperton J.A., Martin S.R., Smerdon S.J., Gamblin S.J., Bayley P.M. Biochemistry 41:14669-14679(2002) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 294-318 IN COMPLEX WITH CALMODULIN, DOMAIN.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L24907 mRNA. Translation: AAA19670.1. Frameshift.
L26288 mRNA. Translation: AAA66944.1.
BC071177 mRNA. Translation: AAH71177.1.

IPI

IPI00209064.

PIR

S50193.

RefSeq

NP_604463.1. NM_134468.1.

UniGene

Rn.11018.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1A06	X-ray	2.50	A	1-322	[»]
1MXE	X-ray	1.70	E/F	294-318	[»]
2L7L	NMR	-	B	299-320	[»]

ProteinModelPortal

Q63450.

SMR

Q63450. Positions 10-316.

ModBase

Search...

Protein-protein interaction databases

MINT

MINT-3375300.

STRING

10116.ENSRNOP00000033456.

PTM databases

PhosphoSite

Q63450.

Proteomic databases

PRIDE

Q63450.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENSRNOT00000029728; ENSRNOP00000033456; ENSRNOG00000021781.

GeneID

171503.

KEGG

rno:171503.

UCSC

RGD:629473. rat.

Organism-specific databases

CTD

8536.

RGD

629473. Camk1.

Phylogenomic databases

eggNOG

COG0515.

GeneTree

ENSGT00670000097661.

HOVERGEN

HBG108055.

KO

K08794.

Enzyme and pathway databases

BRENDA

2.7.11.17. 5301.

Gene expression databases

Genevestigator

Q63450.

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

EvolutionaryTrace

Q63450.

NextBio

622477.

Entry information

Entry name

KCC1A_RAT

Accession

Primary (citable) accession number: Q63450
Secondary accession number(s): Q63084

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	July 15, 1998
Last modified:	April 3, 2013
This is version 119 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program