Reviewed, UniProtKB/Swiss-Prot P97756 (KKCC1_RAT)

Names and origin

Protein names

Recommended name:
    Calcium/calmodulin-dependent protein kinase kinase 1
      Short name=CaMKK 1
    EC=2.7.11.17
Alternative name(s):
    Calcium/calmodulin-dependent protein kinase kinase alpha
      Short name=CaM-kinase kinase alpha
      Short name=CaM-KK alpha
      Short name=CaMKK alpha
    alpha CaMKK
    CaM-kinase IV kinase

Gene names

Name:

Camkk1

Organism

Rattus norvegicus (Rat)

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	505 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Calcium/calmodulin-dependent protein kinase that belongs to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Phosphorylates CAMK1, CAMK1D, CAMK1G and CAMK4. Involved in regulating cell apoptosis. Promotes cell survival by phosphorylating AKT1/PKB that inhibits pro-apoptotic BAD/Bcl2-antagonist of cell death. Ref.1 Ref.3 Ref.7
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Enzyme regulation	Activated by Ca2+/calmodulin. Binding of calmodulin may releave intrasteric autoinhibition. Partially inhibited upon phosphorylation by PRCAKA/PKA. May be regulated through phosphorylation by CAMK1 and CAMK4. Ref.1
Subunit structure	Interacts with CAMK4 and calmodulin. Ref.1 Ref.9
Subcellular location	Cytoplasm. Nucleus. Ref.4 Ref.10
Tissue specificity	Mostly expressed in the brain with higher levels in cortex and hippocampus. Lower expression levels were detected in striatum, nucleus accumbens and cerebellum (at protein level). Abundant in forebrain, weaker in cerebellum and also detected in thymus and spleen. Ref.1 Ref.8
Domain	The autoinhibitory domain overlaps with the calmodulin binding region and may be involved in intrasteric autoinhibition. Ref.9 The RP domain (arginine/proline-rich) is involved in the recognition of CAMKI and CAMK4 as substrates. Ref.9
Post-translational modification	Appears to be autophosphoryated. Phosphorylated at multiple sites by PRCAKA/PKA. Phosphorylation of Ser-458 is blocked upon binding to Ca2+/calmodulin. May be phosphorylated by CAMK1 and CAMK4. Ref.3 Ref.7 Ref.8 Ref.6
Sequence similarities	Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Cytoplasm Nucleus
Ligand	ATP-binding Calmodulin-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	activation of protein kinase activity Inferred from direct assay. Source: RGD protein amino acid phosphorylation Traceable author statement. Source: RGD
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell soluble fraction Inferred from direct assay. Source: RGD
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 direct assay. Source: RGD
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 505

505

Calcium/calmodulin-dependent protein kinase kinase 1

PRO_0000086143

Regions

Domain

128 – 409

282

Protein kinase

Nucleotide binding

134 – 142

9

ATP By similarity

Region

167 – 189

23

RP domain

Region

435 – 440

6

Autoinhibitory domain

Region

438 – 463

26

Calmodulin-binding

Sites

Active site

275

1

Proton acceptor By similarity

Binding site

157

1

ATP By similarity

Amino acid modifications

Modified residue

74

1

Phosphoserine Ref.8

Modified residue

108

1

Phosphothreonine Ref.8 Ref.6

Modified residue

458

1

Phosphoserine Ref.6

Modified residue

475

1

Phosphoserine By similarity

Modified residue

492

1

Phosphoserine By similarity

Experimental info

Mutagenesis

74

1

S → A: Decrease in phosphorylation by PKA. Ref.8

Mutagenesis

108

1

T → A: Decrease in phosphorylation and partial inhibition by PKA. Almost loss of inhibition by PKA; when associated with A-458. Ref.8 Ref.6

Mutagenesis

172

1

R → E: Loss of substrate recognition and interaction with CAMK4. Ref.9

Mutagenesis

177

1

R → E: Loss of substrate recognition and interaction with CAMK4. Ref.9

Mutagenesis

458

1

S → A: Decrease in phosphorylation and partial inhibition by PKA. Almost loss of inhibition by PKA; when associated with A-108. Ref.6

Mutagenesis

459

1

F → D: Loss of binding to Ca(2+)/calmodulin. Ref.11

Mutagenesis

463

1

F → D: Loss of binding to Ca(2+)/calmodulin. Ref.11

Sequence conflict

45

1

P → S in AAC42070. Ref.1

Sequence conflict

81

1

G → E in AAC42070. Ref.1

Secondary structure

1

.

.

.

.

.

505

Helix Strand Turn

Details...

Helix

444 – 453

10

Beta strand

455 – 457

3

Sequences

	Sequence		Length	Mass (Da)
	P97756-1 [UniParc]. Last modified May 1, 1997. Version 1. Checksum: 6B268780AC9B67E1	FASTA	505	55,908
	10 20 30 40 50 60 MERSPAVCCQ DPRAELVERV AAISVAHLEE AEEGPEPASN GVDPPPRARA ASVIPGSASR 70 80 90 100 110 120 PTPVRPSLSA RKFSLQERPA GSCLEAQVGP YSTGPASHMS PRAWRRPTIE SHHVAISDTE 130 140 150 160 170 180 DCVQLNQYKL QSEIGKGAYG VVRLAYNERE DRHYAMKVLS KKKLLKQYGF PRRPPPRGSQ 190 200 210 220 230 240 APQGGPAKQL LPLERVYQEI AILKKLDHVN VVKLIEVLDD PAEDNLYLVF DLLRKGPVME 250 260 270 280 290 300 VPCDKPFPEE QARLYLRDII LGLEYLHCQK IVHRDIKPSN LLLGDDGHVK IADFGVSNQF 310 320 330 340 350 360 EGNDAQLSST AGTPAFMAPE AISDTGQSFS GKALDVWATG VTLYCFVYGK CPFIDEYILA 370 380 390 400 410 420 LHRKIKNEAV VFPEEPEVSE ELKDLILKML DKNPETRIGV SDIKLHPWVT KHGEEPLPSE 430 440 450 460 470 480 EEHCSVVEVT EEEVKNSVKL IPSWTTVILV KSMLRKRSFG NPFEPQARRE ERSMSAPGNL 490 500 LLKEGCGEGG KSPELPGVQE DEAAS

References

[1]	"Characterization of a Ca2+/calmodulin-dependent protein kinase cascade. Molecular cloning and expression of calcium/calmodulin-dependent protein kinase kinase." Tokumitsu H., Enslen H., Soderling T.R. J. Biol. Chem. 270:19320-19324(1995) [PubMed: 7642608] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 214-230 AND 291-310, FUNCTION, ENZYME REGULATION, INTERACTION WITH CALMODULIN, TISSUE SPECIFICITY. Tissue: Brain.
[2]	"Evidence for the existence of Ca2+/calmodulin-dependent protein kinase IV kinase isoforms in rat brain." Okuno S., Kitani T., Fujisawa H. J. Biochem. 119:1176-1181(1996) [PubMed: 8827455] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[3]	"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: PROTEIN SEQUENCE OF 4-13; 20-38; 50-60; 137-148; 196-210; 275-288; 291-311; 333-340; 351-360; 365-382; 389-397; 405-408; 440-444; 458-468 AND 473-478, FUNCTION IN PHOSPHORYLATION OF CAMK1 AND CAMK4, AUTOPHOSPHORYLATION.
[4]	"Distribution of Ca2+/calmodulin-dependent protein kinase kinase alpha in the rat central nervous system: an immunohistochemical study." Nakamura Y., Okuno S., Kitani T., Otake K., Sato F., Fujisawa H. Neurosci. Lett. 204:61-64(1996) [PubMed: 8929978] [Abstract] Cited for: SUBCELLULAR LOCATION.
[5]	"Calcium/calmodulin-dependent protein kinase kinase: identification of regulatory domains." Tokumitsu H., Wayman G.A., Muramatsu M.-A., Soderling T.R. Biochemistry 36:12823-12827(1997) [PubMed: 9335539] [Abstract] Cited for: CHARACTERIZATION.
[6]	"Inhibitory cross-talk by cAMP kinase on the calmodulin-dependent protein kinase cascade." Wayman G.A., Tokumitsu H., Soderling T.R. J. Biol. Chem. 272:16073-16076(1997) [PubMed: 9195898] [Abstract] Cited for: PHOSPHORYLATION AT THR-108 AND SER-458, MUTAGENESIS OF THR-108 AND SER-458, PHOSPHORYLATION BY PRCAKA.
[7]	"Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway." Yano S., Tokumitsu H., Soderling T.R. Nature 396:584-587(1998) [PubMed: 9859994] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF AKT1.
[8]	"Inhibition of the Ca2+/calmodulin-dependent protein kinase I cascade by cAMP-dependent protein kinase." Matsushita M., Nairn A.C. J. Biol. Chem. 274:10086-10093(1999) [PubMed: 10187789] [Abstract] Cited for: PHOSPHORYLATION AT SER-74 AND THR-108, MUTAGENESIS OF SER-74 AND THR-108, PHOSPHORYLATION BY PRCAKA, TISSUE SPECIFICITY.
[9]	"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: MUTAGENESIS OF ARG-172 AND ARG-177, DOMAIN RP, INTERACTION WITH CAMK4.
[10]	"Distinct immunohistochemical localization of two isoforms of Ca2+/calmodulin-dependent protein kinase kinases in the adult rat brain." Sakagami H., Umemiya M., Saito S., Kondo H. Eur. J. Neurosci. 12:89-99(2000) [PubMed: 10651863] [Abstract] Cited for: SUBCELLULAR LOCATION.
[11]	"A novel target recognition revealed by calmodulin in complex with Ca2+-calmodulin-dependent kinase kinase." Osawa M., Tokumitsu H., Swindells M.B., Kurihara H., Orita M., Shibanuma T., Furuya T., Ikura M. Nat. Struct. Biol. 6:819-824(1999) [PubMed: 10467092] [Abstract] Cited for: STRUCTURE BY NMR OF 438-463 IN COMPLEX WITH CA(2+)/CALMODULIN, MUTAGENESIS OF PHE-459 AND PHE-463.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

L42810 mRNA. Translation: AAC42070.1.
AB023658 mRNA. Translation: BAA75246.1.
S83194 mRNA. Translation: AAB46910.1.

IPI

IPI00207573.

PIR

A57156.

RefSeq

NP_113850.1.

UniGene

Rn.4851

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1CKK	NMR	-	B	438-463	[»]

ModBase

Search...

Protein-protein interaction databases

STRING

P97756.

PTM databases

PhosphoSite

P97756.

Genome annotation databases

Ensembl

ENSRNOT00000025009; ENSRNOP00000025009; ENSRNOG00000018242; Rattus norvegicus. [Genome view]

GeneID

60341.

KEGG

rno:60341.

UCSC

NM_031662. rat.

Organism-specific databases

CTD

60341.

RGD

62023. Camkk1.

Phylogenomic databases

HOVERGEN

P97756.

Enzyme and pathway databases

BRENDA

2.7.11.17. 248.

Gene expression databases

Genevestigator

P97756.

GermOnline

ENSRNOG00000018242. Rattus norvegicus.

Family and domain databases

InterPro

IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_BS.
IPR017442. Se/Thr_pkinase-rel.
IPR008271. Ser_thr_pkin_AS.
IPR002290. Ser_thr_pkinase.
[Graphical view]

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

ProDom

PD000001. Prot_kinase. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00220. S_TKc. 1 hit.
[Graphical view]

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

611998.

Entry information

Entry name

KKCC1_RAT

Accession

Primary (citable) accession number: P97756
Secondary accession number(s): Q64572, Q794E3

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 7, 2004
Last sequence update:	May 1, 1997
Last modified:	October 13, 2009
This is version 73 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)