KKCC1_RAT
ID KKCC1_RAT Reviewed; 505 AA.
AC P97756; Q64572; Q794E3;
DT 07-DEC-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1997, sequence version 1.
DT 03-AUG-2022, entry version 151.
DE RecName: Full=Calcium/calmodulin-dependent protein kinase kinase 1;
DE Short=CaM-KK 1;
DE Short=CaM-kinase kinase 1;
DE Short=CaMKK 1;
DE EC=2.7.11.17;
DE AltName: Full=CaM-kinase IV kinase;
DE AltName: Full=Calcium/calmodulin-dependent protein kinase kinase alpha;
DE Short=CaM-KK alpha;
DE Short=CaM-kinase kinase alpha;
DE Short=CaMKK alpha;
GN Name=Camkk1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 214-230 AND 291-310,
RP FUNCTION, ACTIVITY REGULATION, INTERACTION WITH CALMODULIN, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=7642608; DOI=10.1074/jbc.270.33.19320;
RA Tokumitsu H., Enslen H., Soderling T.R.;
RT "Characterization of a Ca2+/calmodulin-dependent protein kinase cascade.
RT Molecular cloning and expression of calcium/calmodulin-dependent protein
RT kinase kinase.";
RL J. Biol. Chem. 270:19320-19324(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=8827455; DOI=10.1093/oxfordjournals.jbchem.a021365;
RA Okuno S., Kitani T., Fujisawa H.;
RT "Evidence for the existence of Ca2+/calmodulin-dependent protein kinase IV
RT kinase isoforms in rat brain.";
RL J. Biochem. 119:1176-1181(1996).
RN [3]
RP PROTEIN SEQUENCE OF 4-13; 20-38; 50-60; 137-148; 196-210; 275-288; 291-311;
RP 333-340; 351-360; 365-382; 389-397; 405-408; 440-444; 458-468 AND 473-478,
RP FUNCTION IN PHOSPHORYLATION OF CAMK1 AND CAMK4, AND AUTOPHOSPHORYLATION.
RX PubMed=8631893; DOI=10.1074/jbc.271.18.10806;
RA Edelman A.M., Mitchelhill K.I., Selbert M.A., Anderson K.A., Hook S.S.,
RA Stapleton D., Goldstein E.G., Means A.R., Kemp B.E.;
RT "Multiple Ca(2+)-calmodulin-dependent protein kinase kinases from rat
RT brain. Purification, regulation by Ca(2+)-calmodulin, and partial amino
RT acid sequence.";
RL J. Biol. Chem. 271:10806-10810(1996).
RN [4]
RP SUBCELLULAR LOCATION.
RX PubMed=8929978; DOI=10.1016/0304-3940(96)12317-x;
RA Nakamura Y., Okuno S., Kitani T., Otake K., Sato F., Fujisawa H.;
RT "Distribution of Ca2+/calmodulin-dependent protein kinase kinase alpha in
RT the rat central nervous system: an immunohistochemical study.";
RL Neurosci. Lett. 204:61-64(1996).
RN [5]
RP CHARACTERIZATION, AND REGION.
RX PubMed=9335539; DOI=10.1021/bi971348i;
RA Tokumitsu H., Wayman G.A., Muramatsu M.-A., Soderling T.R.;
RT "Calcium/calmodulin-dependent protein kinase kinase: identification of
RT regulatory domains.";
RL Biochemistry 36:12823-12827(1997).
RN [6]
RP PHOSPHORYLATION AT THR-108 AND SER-458, MUTAGENESIS OF THR-108 AND SER-458,
RP AND PHOSPHORYLATION BY PRCAKA.
RX PubMed=9195898; DOI=10.1074/jbc.272.26.16073;
RA Wayman G.A., Tokumitsu H., Soderling T.R.;
RT "Inhibitory cross-talk by cAMP kinase on the calmodulin-dependent protein
RT kinase cascade.";
RL J. Biol. Chem. 272:16073-16076(1997).
RN [7]
RP FUNCTION IN PHOSPHORYLATION OF AKT1.
RX PubMed=9859994; DOI=10.1038/25147;
RA Yano S., Tokumitsu H., Soderling T.R.;
RT "Calcium promotes cell survival through CaM-K kinase activation of the
RT protein-kinase-B pathway.";
RL Nature 396:584-587(1998).
RN [8]
RP PHOSPHORYLATION AT SER-74 AND THR-108, MUTAGENESIS OF SER-74 AND THR-108,
RP PHOSPHORYLATION BY PRCAKA, AND TISSUE SPECIFICITY.
RX PubMed=10187789; DOI=10.1074/jbc.274.15.10086;
RA Matsushita M., Nairn A.C.;
RT "Inhibition of the Ca2+/calmodulin-dependent protein kinase I cascade by
RT cAMP-dependent protein kinase.";
RL J. Biol. Chem. 274:10086-10093(1999).
RN [9]
RP MUTAGENESIS OF ARG-172 AND ARG-177, DOMAIN RP, AND INTERACTION WITH CAMK4.
RX PubMed=10336483; DOI=10.1074/jbc.274.22.15803;
RA Tokumitsu H., Takahashi N., Eto K., Yano S., Soderling T.R.,
RA Muramatsu M.-A.;
RT "Substrate recognition by Ca2+/Calmodulin-dependent protein kinase kinase.
RT Role of the arg-pro-rich insert domain.";
RL J. Biol. Chem. 274:15803-15810(1999).
RN [10]
RP SUBCELLULAR LOCATION.
RX PubMed=10651863; DOI=10.1046/j.1460-9568.2000.00883.x;
RA Sakagami H., Umemiya M., Saito S., Kondo H.;
RT "Distinct immunohistochemical localization of two isoforms of
RT Ca2+/calmodulin-dependent protein kinase kinases in the adult rat brain.";
RL Eur. J. Neurosci. 12:89-99(2000).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-458 AND SER-475, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [12]
RP STRUCTURE BY NMR OF 438-463 IN COMPLEX WITH CA(2+)/CALMODULIN, MUTAGENESIS
RP OF PHE-459 AND PHE-463, AND REGION.
RX PubMed=10467092; DOI=10.1038/12271;
RA Osawa M., Tokumitsu H., Swindells M.B., Kurihara H., Orita M.,
RA Shibanuma T., Furuya T., Ikura M.;
RT "A novel target recognition revealed by calmodulin in complex with Ca2+-
RT calmodulin-dependent kinase kinase.";
RL Nat. Struct. Biol. 6:819-824(1999).
CC -!- FUNCTION: Calcium/calmodulin-dependent protein kinase that belongs to a
CC proposed calcium-triggered signaling cascade involved in a number of
CC cellular processes. Phosphorylates CAMK1, CAMK1D, CAMK1G and CAMK4.
CC Involved in regulating cell apoptosis. Promotes cell survival by
CC phosphorylating AKT1/PKB that inhibits pro-apoptotic BAD/Bcl2-
CC antagonist of cell death. {ECO:0000269|PubMed:7642608,
CC ECO:0000269|PubMed:8631893, ECO:0000269|PubMed:9859994}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.17;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.17;
CC -!- ACTIVITY REGULATION: Activated by Ca(2+)/calmodulin. Binding of
CC calmodulin may relieve intrasteric autoinhibition. Partially inhibited
CC upon phosphorylation by PRCAKA/PKA. May be regulated through
CC phosphorylation by CAMK1 and CAMK4. {ECO:0000269|PubMed:7642608}.
CC -!- SUBUNIT: Interacts with CAMK4 and calmodulin.
CC {ECO:0000269|PubMed:10336483, ECO:0000269|PubMed:10467092,
CC ECO:0000269|PubMed:7642608}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus.
CC -!- TISSUE SPECIFICITY: Mostly expressed in the brain with higher levels in
CC cortex and hippocampus. Lower expression levels were detected in
CC striatum, nucleus accumbens and cerebellum (at protein level). Abundant
CC in forebrain, weaker in cerebellum and also detected in thymus and
CC spleen. {ECO:0000269|PubMed:10187789, ECO:0000269|PubMed:7642608}.
CC -!- DOMAIN: The autoinhibitory domain overlaps with the calmodulin binding
CC region and may be involved in intrasteric autoinhibition.
CC {ECO:0000269|PubMed:10336483}.
CC -!- DOMAIN: The RP domain (arginine/proline-rich) is involved in the
CC recognition of CAMKI and CAMK4 as substrates.
CC {ECO:0000269|PubMed:10336483}.
CC -!- PTM: Appears to be autophosphorylated. Phosphorylated at multiple sites
CC by PRCAKA/PKA. Phosphorylation of Ser-458 is blocked upon binding to
CC Ca(2+)/calmodulin. May be phosphorylated by CAMK1 and CAMK4.
CC {ECO:0000269|PubMed:10187789, ECO:0000269|PubMed:9195898}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Ser/Thr protein
CC kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.
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DR EMBL; L42810; AAC42070.1; -; mRNA.
DR EMBL; AB023658; BAA75246.1; -; mRNA.
DR EMBL; S83194; AAB46910.1; -; mRNA.
DR PIR; A57156; A57156.
DR RefSeq; NP_113850.1; NM_031662.1.
DR PDB; 1CKK; NMR; -; B=438-463.
DR PDBsum; 1CKK; -.
DR AlphaFoldDB; P97756; -.
DR BMRB; P97756; -.
DR SMR; P97756; -.
DR BioGRID; 248789; 3.
DR IntAct; P97756; 4.
DR MINT; P97756; -.
DR STRING; 10116.ENSRNOP00000025009; -.
DR iPTMnet; P97756; -.
DR PhosphoSitePlus; P97756; -.
DR PaxDb; P97756; -.
DR GeneID; 60341; -.
DR KEGG; rno:60341; -.
DR CTD; 84254; -.
DR RGD; 62023; Camkk1.
DR eggNOG; KOG0585; Eukaryota.
DR InParanoid; P97756; -.
DR OrthoDB; 1044255at2759; -.
DR PhylomeDB; P97756; -.
DR BRENDA; 2.7.11.17; 5301.
DR Reactome; R-RNO-111932; CaMK IV-mediated phosphorylation of CREB.
DR Reactome; R-RNO-442729; CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde.
DR Reactome; R-RNO-9619229; Activation of RAC1 downstream of NMDARs.
DR EvolutionaryTrace; P97756; -.
DR PRO; PR:P97756; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005516; F:calmodulin binding; IDA:RGD.
DR GO; GO:0004683; F:calmodulin-dependent protein kinase activity; IDA:RGD.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IBA:GO_Central.
DR GO; GO:0032147; P:activation of protein kinase activity; IDA:RGD.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0045860; P:positive regulation of protein kinase activity; IDA:RGD.
DR GO; GO:0006468; P:protein phosphorylation; TAS:RGD.
DR IDEAL; IID50177; -.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Calmodulin-binding; Cytoplasm;
KW Direct protein sequencing; Kinase; Methylation; Nucleotide-binding;
KW Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase.
FT CHAIN 1..505
FT /note="Calcium/calmodulin-dependent protein kinase kinase
FT 1"
FT /id="PRO_0000086143"
FT DOMAIN 128..409
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 27..66
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 167..189
FT /note="RP domain"
FT /evidence="ECO:0000269|PubMed:10336483"
FT REGION 435..440
FT /note="Autoinhibitory domain"
FT /evidence="ECO:0000269|PubMed:10336483,
FT ECO:0000269|PubMed:9335539"
FT REGION 438..463
FT /note="Calmodulin-binding"
FT /evidence="ECO:0000269|PubMed:10467092,
FT ECO:0000269|PubMed:9335539"
FT REGION 460..505
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 275
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 134..142
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 157
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 67
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N5S9"
FT MOD_RES 74
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:10187789"
FT MOD_RES 78
FT /note="Asymmetric dimethylarginine"
FT /evidence="ECO:0000250|UniProtKB:Q8VBY2"
FT MOD_RES 100
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8VBY2"
FT MOD_RES 108
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:10187789,
FT ECO:0000269|PubMed:9195898"
FT MOD_RES 458
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:9195898,
FT ECO:0007744|PubMed:22673903"
FT MOD_RES 475
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 492
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N5S9"
FT MUTAGEN 74
FT /note="S->A: Decrease in phosphorylation by PKA."
FT /evidence="ECO:0000269|PubMed:10187789"
FT MUTAGEN 108
FT /note="T->A: Decrease in phosphorylation and partial
FT inhibition by PKA. Almost loss of inhibition by PKA; when
FT associated with A-458."
FT /evidence="ECO:0000269|PubMed:10187789,
FT ECO:0000269|PubMed:9195898"
FT MUTAGEN 172
FT /note="R->E: Loss of substrate recognition and interaction
FT with CAMK4."
FT /evidence="ECO:0000269|PubMed:10336483"
FT MUTAGEN 177
FT /note="R->E: Loss of substrate recognition and interaction
FT with CAMK4."
FT /evidence="ECO:0000269|PubMed:10336483"
FT MUTAGEN 458
FT /note="S->A: Decrease in phosphorylation and partial
FT inhibition by PKA. Almost loss of inhibition by PKA; when
FT associated with A-108."
FT /evidence="ECO:0000269|PubMed:9195898"
FT MUTAGEN 459
FT /note="F->D: Loss of binding to Ca(2+)/calmodulin."
FT /evidence="ECO:0000269|PubMed:10467092"
FT MUTAGEN 463
FT /note="F->D: Loss of binding to Ca(2+)/calmodulin."
FT /evidence="ECO:0000269|PubMed:10467092"
FT CONFLICT 45
FT /note="P -> S (in Ref. 1; AAC42070)"
FT /evidence="ECO:0000305"
FT CONFLICT 81
FT /note="G -> E (in Ref. 1; AAC42070)"
FT /evidence="ECO:0000305"
FT HELIX 444..453
FT /evidence="ECO:0007829|PDB:1CKK"
FT STRAND 455..457
FT /evidence="ECO:0007829|PDB:1CKK"
SQ SEQUENCE 505 AA; 55908 MW; 6B268780AC9B67E1 CRC64;
MERSPAVCCQ DPRAELVERV AAISVAHLEE AEEGPEPASN GVDPPPRARA ASVIPGSASR
PTPVRPSLSA RKFSLQERPA GSCLEAQVGP YSTGPASHMS PRAWRRPTIE SHHVAISDTE
DCVQLNQYKL QSEIGKGAYG VVRLAYNERE DRHYAMKVLS KKKLLKQYGF PRRPPPRGSQ
APQGGPAKQL LPLERVYQEI AILKKLDHVN VVKLIEVLDD PAEDNLYLVF DLLRKGPVME
VPCDKPFPEE QARLYLRDII LGLEYLHCQK IVHRDIKPSN LLLGDDGHVK IADFGVSNQF
EGNDAQLSST AGTPAFMAPE AISDTGQSFS GKALDVWATG VTLYCFVYGK CPFIDEYILA
LHRKIKNEAV VFPEEPEVSE ELKDLILKML DKNPETRIGV SDIKLHPWVT KHGEEPLPSE
EEHCSVVEVT EEEVKNSVKL IPSWTTVILV KSMLRKRSFG NPFEPQARRE ERSMSAPGNL
LLKEGCGEGG KSPELPGVQE DEAAS
