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Protein

Calcium/calmodulin-dependent protein kinase kinase 2

Gene

Camkk2

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Calcium/calmodulin-dependent protein kinase belonging to a proposed calcium-triggered signaling cascade involved in a number of cellular processes. Phosphorylates CAMK1 and CAMK4. Phosphorylates CAMK1D (By similarity). Seems to be involved in hippocampal activation of CREB1 (By similarity). Efficiently phosphorylates 5'-AMP-activated protein kinase (AMPK) trimer, including that consisting of PRKAA1, PRKAB1 and PRKAG1. This phosphorylation is stimulated in response to Ca2+ signals. May play a role in neurite growth. Isoform 2 may promote neurite elongation, while isoform 1 may promoter neurite branching.By similarity4 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Activated by Ca2+/calmodulin. Binding of calmodulin may relieve intrasteric autoinhibition. Autophosphorylation does not alter activity or regulation by Ca2+/calmodulin. In part, activity is independent on Ca2+/calmodulin.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei193 – 1931ATPPROSITE-ProRule annotation
Active sitei311 – 3111Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi170 – 1789ATPPROSITE-ProRule annotation

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • calcium ion binding Source: UniProtKB
  • calmodulin binding Source: RGD
  • calmodulin-dependent protein kinase activity Source: RGD
  • protein kinase activator activity Source: RGD
  • protein kinase activity Source: RGD

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Ligandi

ATP-binding, Calmodulin-binding, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Calcium/calmodulin-dependent protein kinase kinase 2 (EC:2.7.11.17)
Short name:
CaM-KK 2
Short name:
CaM-kinase kinase 2
Short name:
CaMKK 2
Alternative name(s):
Calcium/calmodulin-dependent protein kinase kinase beta
Short name:
CaM-KK beta
Short name:
CaM-kinase kinase beta
Short name:
CaMKK beta
Gene namesi
Name:Camkk2
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi620092. Camkk2.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell projection, Cytoplasm, Nucleus

Pathology & Biotechi

Chemistry

ChEMBLiCHEMBL1795115.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methionineiRemovedBy similarity
Chaini2 – 587586Calcium/calmodulin-dependent protein kinase kinase 2PRO_0000086146Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylserineBy similarity
Modified residuei99 – 991PhosphoserineBy similarity
Modified residuei128 – 1281PhosphoserineBy similarity
Modified residuei132 – 1321PhosphoserineBy similarity
Modified residuei136 – 1361PhosphoserineBy similarity
Modified residuei494 – 4941PhosphoserineCombined sources
Modified residuei510 – 5101PhosphoserineCombined sources
Modified residuei571 – 5711PhosphoserineBy similarity

Post-translational modificationi

Phosphorylated by PKA (By similarity). Each isoform may show a different pattern of phosphorylation (By similarity). Autophosphorylated.By similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

PaxDbiO88831.
PRIDEiO88831.

PTM databases

iPTMnetiO88831.
PhosphoSiteiO88831.
SwissPalmiO88831.

Expressioni

Tissue specificityi

Mainly expressed in brain, but detected in all tissues tested (at protein level). In the brain, isoform 1 may be predominant. with high levels in the cerebellum and hippocampus, although isoform 3 is detectable. Isoform 3 is also expressed in lung.1 Publication

Interactioni

Subunit structurei

Interacts with calmodulin.1 Publication

GO - Molecular functioni

  • calmodulin binding Source: RGD

Protein-protein interaction databases

BioGridi249725. 6 interactions.
STRINGi10116.ENSRNOP00000001774.

Structurei

3D structure databases

ProteinModelPortaliO88831.
SMRiO88831. Positions 474-499.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini164 – 445282Protein kinasePROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni203 – 22523RP domainAdd
BLAST
Regioni471 – 4766Autoinhibitory domainBy similarity
Regioni474 – 49926Calmodulin-bindingBy similarityAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi110 – 1134Poly-Ser
Compositional biasi548 – 5514Poly-Gly

Domaini

The autoinhibitory domain overlaps with the calmodulin binding region and may be involved in intrasteric autoinhibition.
The RP domain (arginine/proline-rich) is involved in the recognition of CAMKI and CAMK4 as substrates.By similarity

Sequence similaritiesi

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0585. Eukaryota.
ENOG410YHHF. LUCA.
HOGENOMiHOG000007846.
HOVERGENiHBG052262.
InParanoidiO88831.
KOiK07359.
PhylomeDBiO88831.

Family and domain databases

InterProiIPR020636. Ca/CaM-dep_Ca-dep_prot_Kinase.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PANTHERiPTHR24347. PTHR24347. 1 hit.
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 2 hits.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O88831-1) [UniParc]FASTAAdd to basket

Also known as: CAMKK2+E16

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MSSCVSSQPT SDRAAPQDEL GSGGVSRESQ KPCEALRGLS SLSIHLGMES
60 70 80 90 100
FIVVTECEPG RGVDLSLARD QPLEADGQEL PLDASEPESR SLLSGGKMSL
110 120 130 140 150
QERSQGGPAS SSSLDMNGRC ICPSLSYSPA SSPQSSPRMP RRPTVESHHV
160 170 180 190 200
SITGLQDCVQ LNQYTLKDEI GKGSYGVVKL AYNENDNTYY AMKVLSKKKL
210 220 230 240 250
IRQAGFPRRP PPRGTRPAPG GCIQPRGPIE QVYQEIAILK KLDHPNVVKL
260 270 280 290 300
VEVLDDPNED HLYMVFELVN QGPVMEVPTL KPLSEDQARF YFQDLIKGIE
310 320 330 340 350
YLHYQKIIHR DIKPSNLLVG EDGHIKIADF GVSNEFKGSD ALLSNTVGTP
360 370 380 390 400
AFMAPESLSE TRKIFSGKAL DVWAMGVTLY CFVFGQCPFM DERIMCLHSK
410 420 430 440 450
IKSQALEFPD QPDIAEDLKD LITRMLDKNP ESRIVVPEIK LHPWVTRHGA
460 470 480 490 500
EPLPSEDENC TLVEVTEEEV ENSVKHIPSL ATVILVKTMI RKRSFGNPFE
510 520 530 540 550
GSRREERSLS APGNLLTKKP TREWEPLSEP KEARQRRQPP GPRASPCGGG
560 570 580
GSALVKGGPC VESCGAPAPG SPPRTPPQQP EEAMEPE
Length:587
Mass (Da):64,446
Last modified:November 1, 1998 - v1
Checksum:iC9E49B72578F3971
GO
Isoform 2 (identifier: O88831-2) [UniParc]FASTAAdd to basket

Also known as: CAMKK2-E16

The sequence of this isoform differs from the canonical sequence as follows:
     519-587: KPTREWEPLS...QQPEEAMEPE → QGSEDSLRGPEPAPVGEEEVLL

Show »
Length:540
Mass (Da):59,558
Checksum:i8E4D167BB8D8888C
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti180 – 1801L → S AA sequence (PubMed:8631893).Curated
Sequence conflicti245 – 2451P → V AA sequence (PubMed:8631893).Curated
Sequence conflicti300 – 3001Missing AA sequence (PubMed:8631893).Curated
Sequence conflicti465 – 4651V → S AA sequence (PubMed:8631893).Curated
Sequence conflicti468 – 4681E → T AA sequence (PubMed:8631893).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei519 – 58769KPTRE…AMEPE → QGSEDSLRGPEPAPVGEEEV LL in isoform 2. CuratedVSP_046047Add
BLAST

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB018081 mRNA. Translation: BAA33524.1.
PIRiJC5669.
RefSeqiNP_112628.1. NM_031338.1. [O88831-1]
UniGeneiRn.229208.

Genome annotation databases

GeneIDi83506.
KEGGirno:83506.
UCSCiRGD:620092. rat. [O88831-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB018081 mRNA. Translation: BAA33524.1.
PIRiJC5669.
RefSeqiNP_112628.1. NM_031338.1. [O88831-1]
UniGeneiRn.229208.

3D structure databases

ProteinModelPortaliO88831.
SMRiO88831. Positions 474-499.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi249725. 6 interactions.
STRINGi10116.ENSRNOP00000001774.

Chemistry

ChEMBLiCHEMBL1795115.

PTM databases

iPTMnetiO88831.
PhosphoSiteiO88831.
SwissPalmiO88831.

Proteomic databases

PaxDbiO88831.
PRIDEiO88831.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi83506.
KEGGirno:83506.
UCSCiRGD:620092. rat. [O88831-1]

Organism-specific databases

CTDi10645.
RGDi620092. Camkk2.

Phylogenomic databases

eggNOGiKOG0585. Eukaryota.
ENOG410YHHF. LUCA.
HOGENOMiHOG000007846.
HOVERGENiHBG052262.
InParanoidiO88831.
KOiK07359.
PhylomeDBiO88831.

Miscellaneous databases

NextBioi615936.
PROiO88831.

Family and domain databases

InterProiIPR020636. Ca/CaM-dep_Ca-dep_prot_Kinase.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PANTHERiPTHR24347. PTHR24347. 1 hit.
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 2 hits.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Molecular cloning of Ca2+/calmodulin-dependent protein kinase kinase beta."
    Kitani T., Okuno S., Fujisawa H.
    J. Biochem. 122:243-250(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
    Tissue: Cerebellum.
  2. "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: PROTEIN SEQUENCE OF 180-184; 227-280; 290-294; 298-306; 327-335; 338-355; 403-418; 425-429; 434-445; 448-469 AND 494-503, FUNCTION IN PHOSPHORYLATION OF CAMK1 AND CAMK4.
  3. "Components of a calmodulin-dependent protein kinase cascade. Molecular cloning, functional characterization and cellular localization of Ca2+/calmodulin-dependent protein kinase kinase beta."
    Anderson K.A., Means R.L., Huang Q.-H., Kemp B.E., Goldstein E.G., Selbert M.A., Edelman A.M., Fremeau R.T., Means A.R.
    J. Biol. Chem. 273:31880-31889(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: CHARACTERIZATION, INTERACTION WITH CALMODULIN, FUNCTION IN PHOSPHORYLATION OF CAMK1 AND CAMK4, AUTOPHOSPHORYLATION.
  4. "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] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION.
  5. "Ca(2+)/CaM-dependent kinases: from activation to function."
    Hook S.S., Means A.R.
    Annu. Rev. Pharmacol. Toxicol. 41:471-505(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION.
  6. "Characterization of the CaMKKbeta-AMPK signaling complex."
    Green M.F., Anderson K.A., Means A.R.
    Cell. Signal. 23:2005-2012(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION.
  7. "Differential effects of PKA-controlled CaMKK2 variants on neuronal differentiation."
    Cao W., Sohail M., Liu G., Koumbadinga G.A., Lobo V.G., Xie J.
    RNA Biol. 8:1061-1072(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, TISSUE SPECIFICITY, IDENTIFICATION OF ISOFORM 2.
  8. "Quantitative maps of protein phosphorylation sites across 14 different rat organs and tissues."
    Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C., Olsen J.V.
    Nat. Commun. 3:876-876(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-494 AND SER-510, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].

Entry informationi

Entry nameiKKCC2_RAT
AccessioniPrimary (citable) accession number: O88831
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 7, 2004
Last sequence update: November 1, 1998
Last modified: May 11, 2016
This is version 123 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.