GenomeNet

Database: UniProt
Entry: Q16566
LinkDB: Q16566
Original site: Q16566 
ID   KCC4_HUMAN              Reviewed;         473 AA.
AC   Q16566; D3DSZ7;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   29-SEP-2021, entry version 195.
DE   RecName: Full=Calcium/calmodulin-dependent protein kinase type IV;
DE            Short=CaMK IV;
DE            EC=2.7.11.17;
DE   AltName: Full=CaM kinase-GR;
GN   Name=CAMK4; Synonyms=CAMK, CAMK-GR, CAMKIV;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=8089075; DOI=10.1093/oxfordjournals.jbchem.a124387;
RA   Kitani T., Okuno S., Fujisawa H.;
RT   "cDNA cloning and expression of human calmodulin-dependent protein kinase
RT   IV.";
RL   J. Biochem. 115:637-640(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Cerebellum, and Thymus;
RX   PubMed=8194751; DOI=10.1016/0378-1119(94)90260-7;
RA   Bland M.M., Monroe R.S., Ohmstede C.A.;
RT   "The cDNA sequence and characterization of the Ca2+/calmodulin-dependent
RT   protein kinase-Gr from human brain and thymus.";
RL   Gene 142:191-197(1994).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Blood;
RX   PubMed=8107230; DOI=10.1128/jvi.68.3.1697-1705.1994;
RA   Mosialos G., Hanissian S.H., Jawahar S., Vara L., Kieff E., Chatila T.A.;
RT   "A Ca2+/calmodulin-dependent protein kinase, CaM kinase-Gr, expressed after
RT   transformation of primary human B lymphocytes by Epstein-Barr virus (EBV)
RT   is induced by the EBV oncogene LMP1.";
RL   J. Virol. 68:1697-1705(1994).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Brain, and Lung;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [6]
RP   TISSUE SPECIFICITY.
RX   PubMed=8397199;
RA   Hanissian S.H., Frangakis M., Bland M.M., Jawahar S., Chatila T.A.;
RT   "Expression of a Ca2+/calmodulin-dependent protein kinase, CaM kinase-Gr,
RT   in human T lymphocytes. Regulation of kinase activity by T cell receptor
RT   signaling.";
RL   J. Biol. Chem. 268:20055-20063(1993).
RN   [7]
RP   FUNCTION, TISSUE SPECIFICITY, DOMAIN AUTOINHIBITORY, AND MUTAGENESIS OF
RP   309-HIS--THR-312 AND 320-PHE-ASN-321.
RX   PubMed=7961813;
RA   Tokumitsu H., Brickey D.A., Glod J., Hidaka H., Sikela J., Soderling T.R.;
RT   "Activation mechanisms for Ca2+/calmodulin-dependent protein kinase IV.
RT   Identification of a brain CaM-kinase IV kinase.";
RL   J. Biol. Chem. 269:28640-28647(1994).
RN   [8]
RP   FUNCTION IN PHOSPHORYLATION OF CREB1, AND SUBCELLULAR LOCATION.
RX   PubMed=8065343; DOI=10.1128/mcb.14.9.6107-6116.1994;
RA   Matthews R.P., Guthrie C.R., Wailes L.M., Zhao X., Means A.R.,
RA   McKnight G.S.;
RT   "Calcium/calmodulin-dependent protein kinase types II and IV differentially
RT   regulate CREB-dependent gene expression.";
RL   Mol. Cell. Biol. 14:6107-6116(1994).
RN   [9]
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=8980227; DOI=10.1016/s0092-8674(00)81816-4;
RA   Bito H., Deisseroth K., Tsien R.W.;
RT   "CREB phosphorylation and dephosphorylation: a Ca(2+)- and stimulus
RT   duration-dependent switch for hippocampal gene expression.";
RL   Cell 87:1203-1214(1996).
RN   [10]
RP   ACTIVITY REGULATION, PHOSPHORYLATION AT SER-12; SER-13 AND THR-200, AND
RP   MUTAGENESIS OF SER-12 AND SER-13.
RX   PubMed=8702940; DOI=10.1074/jbc.271.35.21542;
RA   Chatila T., Anderson K.A., Ho N., Means A.R.;
RT   "A unique phosphorylation-dependent mechanism for the activation of
RT   Ca2+/calmodulin-dependent protein kinase type IV/GR.";
RL   J. Biol. Chem. 271:21542-21548(1996).
RN   [11]
RP   FUNCTION IN PHOSPHORYLATION OF ELK1; JUN AND ATF2, AND MUTAGENESIS OF
RP   THR-200.
RX   PubMed=8855261; DOI=10.1073/pnas.93.20.10803;
RA   Enslen H., Tokumitsu H., Stork P.J., Davis R.J., Soderling T.R.;
RT   "Regulation of mitogen-activated protein kinases by a calcium/calmodulin-
RT   dependent protein kinase cascade.";
RL   Proc. Natl. Acad. Sci. U.S.A. 93:10803-10808(1996).
RN   [12]
RP   FUNCTION IN PHOSPHORYLATION OF STMN1.
RX   PubMed=9154845; DOI=10.1128/mcb.17.6.3459;
RA   Melander Gradin H., Marklund U., Larsson N., Chatila T.A., Gullberg M.;
RT   "Regulation of microtubule dynamics by Ca2+/calmodulin-dependent kinase
RT   IV/Gr-dependent phosphorylation of oncoprotein 18.";
RL   Mol. Cell. Biol. 17:3459-3467(1997).
RN   [13]
RP   FUNCTION IN PHOSPHORYLATION OF MEF2D, AND MUTAGENESIS OF LYS-75.
RX   PubMed=10617605; DOI=10.1074/jbc.275.1.197;
RA   Blaeser F., Ho N., Prywes R., Chatila T.A.;
RT   "Ca(2+)-dependent gene expression mediated by MEF2 transcription factors.";
RL   J. Biol. Chem. 275:197-209(2000).
RN   [14]
RP   TISSUE SPECIFICITY.
RX   PubMed=12065094; DOI=10.1016/s0304-3835(02)00107-6;
RA   Takai N., Miyazaki T., Nishida M., Nasu K., Miyakawa I.;
RT   "Ca(2+)/calmodulin-dependent protein kinase IV expression in epithelial
RT   ovarian cancer.";
RL   Cancer Lett. 183:185-193(2002).
RN   [15]
RP   ACTIVITY REGULATION, INTERACTION WITH PROTEIN PHOSPHATASE 2A,
RP   PHOSPHORYLATION AT THR-200, AND MUTAGENESIS OF 320-PHE-ASN-321.
RX   PubMed=15143065; DOI=10.1074/jbc.m404523200;
RA   Anderson K.A., Noeldner P.K., Reece K., Wadzinski B.E., Means A.R.;
RT   "Regulation and function of the calcium/calmodulin-dependent protein kinase
RT   IV/protein serine/threonine phosphatase 2A signaling complex.";
RL   J. Biol. Chem. 279:31708-31716(2004).
RN   [16]
RP   ACTIVITY REGULATION, AND PROTEIN PHOSPHATASE 2A BINDING DOMAIN.
RX   PubMed=15769749; DOI=10.1074/jbc.m500067200;
RA   Chow F.A., Anderson K.A., Noeldner P.K., Means A.R.;
RT   "The autonomous activity of calcium/calmodulin-dependent protein kinase IV
RT   is required for its role in transcription.";
RL   J. Biol. Chem. 280:20530-20538(2005).
RN   [17]
RP   FUNCTION IN DENDRITIC CELLS LIFESPAN REGULATION, AND DEVELOPMENTAL STAGE.
RX   PubMed=17909078; DOI=10.1182/blood-2007-05-091173;
RA   Illario M., Giardino-Torchia M.L., Sankar U., Ribar T.J., Galgani M.,
RA   Vitiello L., Masci A.M., Bertani F.R., Ciaglia E., Astone D., Maulucci G.,
RA   Cavallo A., Vitale M., Cimini V., Pastore L., Means A.R., Rossi G.,
RA   Racioppi L.;
RT   "Calmodulin-dependent kinase IV links Toll-like receptor 4 signaling with
RT   survival pathway of activated dendritic cells.";
RL   Blood 111:723-731(2008).
RN   [18]
RP   FUNCTION.
RX   PubMed=18829949; DOI=10.1523/jneurosci.2625-08.2008;
RA   Fukushima H., Maeda R., Suzuki R., Suzuki A., Nomoto M., Toyoda H.,
RA   Wu L.J., Xu H., Zhao M.G., Ueda K., Kitamoto A., Mamiya N., Yoshida T.,
RA   Homma S., Masushige S., Zhuo M., Kida S.;
RT   "Upregulation of calcium/calmodulin-dependent protein kinase IV improves
RT   memory formation and rescues memory loss with aging.";
RL   J. Neurosci. 28:9910-9919(2008).
RN   [19]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19413330; DOI=10.1021/ac9004309;
RA   Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT   "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT   refined SCX-based approach.";
RL   Anal. Chem. 81:4493-4501(2009).
RN   [20]
RP   GLYCOSYLATION AT THR-57 SER-58; SER-137; SER-189; SER-344; SER-345 AND
RP   SER-356, PHOSPHORYLATION AT THR-200, IDENTIFICATION BY MASS SPECTROMETRY,
RP   AND MUTAGENESIS OF 57-THR-SER-58 AND SER-189.
RX   PubMed=19506079; DOI=10.1074/jbc.m109.007310;
RA   Dias W.B., Cheung W.D., Wang Z., Hart G.W.;
RT   "Regulation of calcium/calmodulin-dependent kinase IV by O-GlcNAc
RT   modification.";
RL   J. Biol. Chem. 284:21327-21337(2009).
RN   [21]
RP   REVIEW ON FUNCTION, AND REVIEW ON ACTIVITY REGULATION.
RX   PubMed=9920409; DOI=10.1016/s0167-4889(98)00142-6;
RA   Krebs J.;
RT   "Calmodulin-dependent protein kinase IV: regulation of function and
RT   expression.";
RL   Biochim. Biophys. Acta 1448:183-189(1998).
RN   [22]
RP   REVIEW ON FUNCTION IN NEURONAL PLASTICITY.
RX   PubMed=18817731; DOI=10.1016/j.neuron.2008.08.021;
RA   Wayman G.A., Lee Y.S., Tokumitsu H., Silva A.J., Silva A., Soderling T.R.;
RT   "Calmodulin-kinases: modulators of neuronal development and plasticity.";
RL   Neuron 59:914-931(2008).
RN   [23]
RP   REVIEW ON INVOLVEMENT IN IMMUNE AND INFLAMMATORY RESPONSE.
RX   PubMed=18930438; DOI=10.1016/j.it.2008.08.005;
RA   Racioppi L., Means A.R.;
RT   "Calcium/calmodulin-dependent kinase IV in immune and inflammatory
RT   responses: novel routes for an ancient traveller.";
RL   Trends Immunol. 29:600-607(2008).
RN   [24]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-360, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Leukemic T-cell;
RX   PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA   Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA   Rodionov V., Han D.K.;
RT   "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT   reveals system-wide modulation of protein-protein interactions.";
RL   Sci. Signal. 2:RA46-RA46(2009).
RN   [25]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA   Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [26]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Liver;
RX   PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA   Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA   Ye M., Zou H.;
RT   "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT   phosphoproteome.";
RL   J. Proteomics 96:253-262(2014).
RN   [27]
RP   X-RAY CRYSTALLOGRAPHY (2.17 ANGSTROMS) OF 15-340 IN COMPLEX WITH INHIBITOR.
RA   Muniz J.R.C., Rellos P., Gileadi O., Fedorov O., Filippakopoulos P.,
RA   Salah E., Pike A., Phillips C., Niesen F., Shrestha L., Burgess-Brown N.,
RA   Bullock A., Berridge G., Vondelft F., Edwards A.M., Bountra C.,
RA   Arrowsmith C.H., Weigelt J., Knapp S.;
RT   "Crystal structure of human CAMK4 in complex with 4-amino(sulfamoyl-
RT   phenylamino)-triazole-carbothioic acid (2,6-difluoro-phenyl)-amide).";
RL   Submitted (NOV-2008) to the PDB data bank.
RN   [28]
RP   VARIANTS [LARGE SCALE ANALYSIS] GLY-150; ASN-178; ARG-465 AND MET-469.
RX   PubMed=17344846; DOI=10.1038/nature05610;
RA   Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA   Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA   Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA   Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA   Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA   Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA   Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA   Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA   Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA   Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA   Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA   Futreal P.A., Stratton M.R.;
RT   "Patterns of somatic mutation in human cancer genomes.";
RL   Nature 446:153-158(2007).
CC   -!- FUNCTION: Calcium/calmodulin-dependent protein kinase that operates in
CC       the calcium-triggered CaMKK-CaMK4 signaling cascade and regulates,
CC       mainly by phosphorylation, the activity of several transcription
CC       activators, such as CREB1, MEF2D, JUN and RORA, which play pivotal
CC       roles in immune response, inflammation, and memory consolidation. In
CC       the thymus, regulates the CD4(+)/CD8(+) double positive thymocytes
CC       selection threshold during T-cell ontogeny. In CD4 memory T-cells, is
CC       required to link T-cell antigen receptor (TCR) signaling to the
CC       production of IL2, IFNG and IL4 (through the regulation of CREB and
CC       MEF2). Regulates the differentiation and survival phases of osteoclasts
CC       and dendritic cells (DCs). Mediates DCs survival by linking TLR4 and
CC       the regulation of temporal expression of BCL2. Phosphorylates the
CC       transcription activator CREB1 on 'Ser-133' in hippocampal neuron nuclei
CC       and contribute to memory consolidation and long term potentiation (LTP)
CC       in the hippocampus. Can activate the MAP kinases MAPK1/ERK2, MAPK8/JNK1
CC       and MAPK14/p38 and stimulate transcription through the phosphorylation
CC       of ELK1 and ATF2. Can also phosphorylate in vitro CREBBP, PRM2, MEF2A
CC       and STMN1/OP18. {ECO:0000269|PubMed:10617605,
CC       ECO:0000269|PubMed:17909078, ECO:0000269|PubMed:18829949,
CC       ECO:0000269|PubMed:7961813, ECO:0000269|PubMed:8065343,
CC       ECO:0000269|PubMed:8855261, ECO:0000269|PubMed:8980227,
CC       ECO:0000269|PubMed:9154845}.
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 results in conformational change that relieves intrasteric
CC       autoinhibition and allows phosphorylation of Thr-200 within the
CC       activation loop by CaMKK1 or CaMKK2. Phosphorylation of Thr-200 results
CC       in a 10-20-fold increase in total activity to generate
CC       Ca(2+)/calmodulin-independent activity. Autophosphorylation of the N-
CC       terminus Ser-12 and Ser-13 is required for full activation. Inactivated
CC       by protein phosphatase 2A (PPP2CA/PPP2CB) which dephosphorylates Thr-
CC       200, thereby terminating autonomous activity and helping to maintain
CC       the enzyme in its autoinhibited state. {ECO:0000269|PubMed:15143065,
CC       ECO:0000269|PubMed:15769749, ECO:0000269|PubMed:8702940}.
CC   -!- SUBUNIT: Monomer (By similarity). Interacts with protein phosphatase 2A
CC       (PPP2CA/PPP2CB); the interaction is mutually exclusive with binding to
CC       Ca(2+)/calmodulin. {ECO:0000250, ECO:0000269|PubMed:15143065,
CC       ECO:0000269|Ref.27}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Localized in hippocampal
CC       neuron nuclei. In spermatids, associated with chromatin and nuclear
CC       matrix (By similarity). {ECO:0000250}.
CC   -!- TISSUE SPECIFICITY: Expressed in brain, thymus, CD4 T-cells, testis and
CC       epithelial ovarian cancer tissue. {ECO:0000269|PubMed:12065094,
CC       ECO:0000269|PubMed:7961813, ECO:0000269|PubMed:8397199}.
CC   -!- DEVELOPMENTAL STAGE: Expressed during differentiation of monocyte-
CC       derived dendritic cells (at protein level).
CC       {ECO:0000269|PubMed:17909078}.
CC   -!- DOMAIN: The autoinhibitory domain overlaps with the calmodulin binding
CC       region and interacts in the inactive folded state with the catalytic
CC       domain as a pseudosubstrate. {ECO:0000269|PubMed:7961813}.
CC   -!- PTM: Phosphorylated by CaMKK1 and CaMKK2 on Thr-200. Dephosphorylated
CC       by protein phosphatase 2A. Autophosphorylated on Ser-12 and Ser-13.
CC       {ECO:0000269|PubMed:15143065, ECO:0000269|PubMed:19506079,
CC       ECO:0000269|PubMed:8702940}.
CC   -!- PTM: Glycosylation at Ser-189 modulates the phosphorylation of CaMK4 at
CC       Thr-200 and negatively regulates its activity toward CREB1 in basal
CC       conditions and during early inomycin stimulation.
CC       {ECO:0000269|PubMed:15143065, ECO:0000269|PubMed:19506079,
CC       ECO:0000269|PubMed:8702940}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC       protein kinase family. CaMK subfamily. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH16695.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC   ---------------------------------------------------------------------------
CC   Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC   Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC   ---------------------------------------------------------------------------
DR   EMBL; D30742; BAA06403.1; -; mRNA.
DR   EMBL; L17000; AAA35639.1; -; mRNA.
DR   EMBL; L24959; AAA18251.1; -; mRNA.
DR   EMBL; CH471086; EAW49033.1; -; Genomic_DNA.
DR   EMBL; CH471086; EAW49034.1; -; Genomic_DNA.
DR   EMBL; BC016695; AAH16695.2; ALT_INIT; mRNA.
DR   EMBL; BC025687; AAH25687.1; -; mRNA.
DR   CCDS; CCDS4103.1; -.
DR   PIR; A53036; A53036.
DR   RefSeq; NP_001310303.1; NM_001323374.1.
DR   RefSeq; NP_001310304.1; NM_001323375.1.
DR   RefSeq; NP_001735.1; NM_001744.5.
DR   PDB; 2W4O; X-ray; 2.17 A; A=15-340.
DR   PDBsum; 2W4O; -.
DR   SMR; Q16566; -.
DR   BioGRID; 107264; 15.
DR   DIP; DIP-41997N; -.
DR   IntAct; Q16566; 8.
DR   STRING; 9606.ENSP00000282356; -.
DR   BindingDB; Q16566; -.
DR   ChEMBL; CHEMBL2494; -.
DR   DrugBank; DB07676; 3-({[(3S)-3,4-dihydroxybutyl]oxy}amino)-1H,2'H-2,3'-biindol-2'-one.
DR   DrugBank; DB07664; K-00546.
DR   DrugCentral; Q16566; -.
DR   GlyGen; Q16566; 7 sites, 1 O-linked glycan (3 sites).
DR   iPTMnet; Q16566; -.
DR   MetOSite; Q16566; -.
DR   PhosphoSitePlus; Q16566; -.
DR   BioMuta; CAMK4; -.
DR   DMDM; 2499586; -.
DR   EPD; Q16566; -.
DR   jPOST; Q16566; -.
DR   MassIVE; Q16566; -.
DR   MaxQB; Q16566; -.
DR   PaxDb; Q16566; -.
DR   PeptideAtlas; Q16566; -.
DR   PRIDE; Q16566; -.
DR   ProteomicsDB; 60921; -.
DR   Antibodypedia; 2084; 625 antibodies.
DR   DNASU; 814; -.
DR   Ensembl; ENST00000282356; ENSP00000282356; ENSG00000152495.
DR   Ensembl; ENST00000512453; ENSP00000422634; ENSG00000152495.
DR   GeneID; 814; -.
DR   KEGG; hsa:814; -.
DR   UCSC; uc003kpf.4; human.
DR   CTD; 814; -.
DR   DisGeNET; 814; -.
DR   GeneCards; CAMK4; -.
DR   HGNC; HGNC:1464; CAMK4.
DR   HPA; ENSG00000152495; Tissue enhanced (brain, lymphoid tissue).
DR   MIM; 114080; gene.
DR   neXtProt; NX_Q16566; -.
DR   OpenTargets; ENSG00000152495; -.
DR   PharmGKB; PA26050; -.
DR   VEuPathDB; HostDB:ENSG00000152495; -.
DR   eggNOG; KOG0032; Eukaryota.
DR   GeneTree; ENSGT00940000160006; -.
DR   HOGENOM; CLU_000288_63_0_1; -.
DR   InParanoid; Q16566; -.
DR   OMA; AAPEYWI; -.
DR   OrthoDB; 330091at2759; -.
DR   PhylomeDB; Q16566; -.
DR   TreeFam; TF351230; -.
DR   BRENDA; 2.7.11.17; 2681.
DR   PathwayCommons; Q16566; -.
DR   Reactome; R-HSA-111932; CaMK IV-mediated phosphorylation of CREB.
DR   Reactome; R-HSA-2151201; Transcriptional activation of mitochondrial biogenesis.
DR   Reactome; R-HSA-442729; CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde.
DR   Reactome; R-HSA-9022535; Loss of phosphorylation of MECP2 at T308.
DR   Reactome; R-HSA-9022692; Regulation of MECP2 expression and activity.
DR   Reactome; R-HSA-9617324; Negative regulation of NMDA receptor-mediated neuronal transmission.
DR   SignaLink; Q16566; -.
DR   SIGNOR; Q16566; -.
DR   BioGRID-ORCS; 814; 2 hits in 1041 CRISPR screens.
DR   ChiTaRS; CAMK4; human.
DR   EvolutionaryTrace; Q16566; -.
DR   GeneWiki; CAMK4; -.
DR   GenomeRNAi; 814; -.
DR   Pharos; Q16566; Tbio.
DR   PRO; PR:Q16566; -.
DR   Proteomes; UP000005640; Chromosome 5.
DR   RNAct; Q16566; protein.
DR   Bgee; ENSG00000152495; Expressed in caudate nucleus and 164 other tissues.
DR   ExpressionAtlas; Q16566; baseline and differential.
DR   Genevisible; Q16566; HS.
DR   GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR   GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR   GO; GO:0001650; C:fibrillar center; IDA:HPA.
DR   GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR   GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0098794; C:postsynapse; IEA:Ensembl.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0009931; F:calcium-dependent protein serine/threonine kinase activity; IBA:GO_Central.
DR   GO; GO:0005516; F:calmodulin binding; IBA:GO_Central.
DR   GO; GO:0004683; F:calmodulin-dependent protein kinase activity; IDA:CACAO.
DR   GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR   GO; GO:0106311; F:protein threonine kinase activity; IEA:RHEA.
DR   GO; GO:0002250; P:adaptive immune response; IEA:UniProtKB-KW.
DR   GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR   GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR   GO; GO:0007616; P:long-term memory; IGI:UniProtKB.
DR   GO; GO:0043011; P:myeloid dendritic cell differentiation; IMP:UniProtKB.
DR   GO; GO:0018105; P:peptidyl-serine phosphorylation; IBA:GO_Central.
DR   GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB.
DR   GO; GO:0046777; P:protein autophosphorylation; IBA:GO_Central.
DR   GO; GO:0006468; P:protein phosphorylation; TAS:ProtInc.
DR   GO; GO:0045670; P:regulation of osteoclast differentiation; TAS:UniProtKB.
DR   GO; GO:0033081; P:regulation of T cell differentiation in thymus; TAS:UniProtKB.
DR   GO; GO:0007165; P:signal transduction; TAS:ProtInc.
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; Adaptive immunity; ATP-binding; Calcium; Calmodulin-binding;
KW   Cytoplasm; Glycoprotein; Immunity; Inflammatory response; Kinase;
KW   Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW   Serine/threonine-protein kinase; Transferase.
FT   CHAIN           1..473
FT                   /note="Calcium/calmodulin-dependent protein kinase type IV"
FT                   /id="PRO_0000086106"
FT   DOMAIN          46..300
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   NP_BIND         52..60
FT                   /note="ATP"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          305..321
FT                   /note="Autoinhibitory domain"
FT   REGION          306..323
FT                   /note="PP2A-binding"
FT   REGION          322..341
FT                   /note="Calmodulin-binding"
FT                   /evidence="ECO:0000255"
FT   REGION          341..368
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          445..473
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        351..368
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        164
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT                   ECO:0000255|PROSITE-ProRule:PRU10027"
FT   BINDING         75
FT                   /note="ATP"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   MOD_RES         12
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:8702940"
FT   MOD_RES         13
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000269|PubMed:8702940"
FT   MOD_RES         200
FT                   /note="Phosphothreonine; by CaMKK1 and CaMKK2"
FT                   /evidence="ECO:0000269|PubMed:15143065,
FT                   ECO:0000269|PubMed:19506079, ECO:0000269|PubMed:8702940"
FT   MOD_RES         336
FT                   /note="Phosphoserine; by autocatalysis"
FT                   /evidence="ECO:0000250|UniProtKB:P13234"
FT   MOD_RES         341
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P13234"
FT   MOD_RES         360
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19690332"
FT   CARBOHYD        57
FT                   /note="O-linked (GlcNAc) threonine"
FT                   /evidence="ECO:0000269|PubMed:19506079"
FT   CARBOHYD        58
FT                   /note="O-linked (GlcNAc) serine"
FT                   /evidence="ECO:0000269|PubMed:19506079"
FT   CARBOHYD        137
FT                   /note="O-linked (GlcNAc) serine"
FT                   /evidence="ECO:0000269|PubMed:19506079"
FT   CARBOHYD        189
FT                   /note="O-linked (GlcNAc) serine"
FT                   /evidence="ECO:0000269|PubMed:19506079"
FT   CARBOHYD        344
FT                   /note="O-linked (GlcNAc) serine"
FT                   /evidence="ECO:0000269|PubMed:19506079"
FT   CARBOHYD        345
FT                   /note="O-linked (GlcNAc) serine"
FT                   /evidence="ECO:0000269|PubMed:19506079"
FT   CARBOHYD        356
FT                   /note="O-linked (GlcNAc) serine"
FT                   /evidence="ECO:0000269|PubMed:19506079"
FT   VARIANT         150
FT                   /note="E -> G (in a lung adenocarcinoma sample; somatic
FT                   mutation)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040604"
FT   VARIANT         178
FT                   /note="D -> N (in dbSNP:rs35548075)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040605"
FT   VARIANT         465
FT                   /note="Q -> R (in dbSNP:rs56360861)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040606"
FT   VARIANT         469
FT                   /note="I -> M (in a lung large cell carcinoma sample;
FT                   somatic mutation; dbSNP:rs1239950009)"
FT                   /evidence="ECO:0000269|PubMed:17344846"
FT                   /id="VAR_040607"
FT   MUTAGEN         12
FT                   /note="S->A: Loss of activity."
FT                   /evidence="ECO:0000269|PubMed:8702940"
FT   MUTAGEN         13
FT                   /note="S->A: Loss of activity."
FT                   /evidence="ECO:0000269|PubMed:8702940"
FT   MUTAGEN         57..58
FT                   /note="TS->AA: Loss of phosphorylation of CREB1."
FT                   /evidence="ECO:0000269|PubMed:19506079"
FT   MUTAGEN         75
FT                   /note="K->E: Loss of activity; dominant negative form."
FT                   /evidence="ECO:0000269|PubMed:10617605"
FT   MUTAGEN         189
FT                   /note="S->A: Increases phosphorylation of CREB1 2-fold.
FT                   Decreases total O-linked glycosylation 2-fold. Increases
FT                   ATP-binding affinity."
FT                   /evidence="ECO:0000269|PubMed:19506079"
FT   MUTAGEN         200
FT                   /note="T->A: Loss of activation by CaMKK1 or CaMKK2."
FT                   /evidence="ECO:0000269|PubMed:8855261"
FT   MUTAGEN         309..312
FT                   /note="HMDT->DEDD: Fully active Ca2+/CaM-independent
FT                   kinase; when associated with 320-A-A-321."
FT                   /evidence="ECO:0000269|PubMed:7961813"
FT   MUTAGEN         320..321
FT                   /note="FN->DD: Fully active Ca2+/CaM-independent kinase;
FT                   when associated with 309-A--A-312. Loss of interaction with
FT                   PPP2CA/PPP2CB."
FT                   /evidence="ECO:0000269|PubMed:15143065,
FT                   ECO:0000269|PubMed:7961813"
FT   STRAND          36..38
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   HELIX           42..44
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   STRAND          46..54
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   STRAND          56..65
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   TURN            66..68
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   STRAND          71..78
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   HELIX           91..95
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   STRAND          104..109
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   STRAND          111..118
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   HELIX           126..130
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   HELIX           138..157
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   HELIX           167..169
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   STRAND          170..176
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   STRAND          181..183
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   HELIX           205..207
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   HELIX           210..213
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   HELIX           221..236
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   HELIX           247..255
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   TURN            263..268
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   HELIX           271..278
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   HELIX           285..287
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   HELIX           291..296
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   TURN            298..301
FT                   /evidence="ECO:0007829|PDB:2W4O"
FT   HELIX           311..335
FT                   /evidence="ECO:0007829|PDB:2W4O"
SQ   SEQUENCE   473 AA;  51926 MW;  EFEE51E5612326DC CRC64;
     MLKVTVPSCS ASSCSSVTAS AAPGTASLVP DYWIDGSNRD ALSDFFEVES ELGRGATSIV
     YRCKQKGTQK PYALKVLKKT VDKKIVRTEI GVLLRLSHPN IIKLKEIFET PTEISLVLEL
     VTGGELFDRI VEKGYYSERD AADAVKQILE AVAYLHENGI VHRDLKPENL LYATPAPDAP
     LKIADFGLSK IVEHQVLMKT VCGTPGYCAP EILRGCAYGP EVDMWSVGII TYILLCGFEP
     FYDERGDQFM FRRILNCEYY FISPWWDEVS LNAKDLVRKL IVLDPKKRLT TFQALQHPWV
     TGKAANFVHM DTAQKKLQEF NARRKLKAAV KAVVASSRLG SASSSHGSIQ ESHKASRDPS
     PIQDGNEDMK AIPEGEKIQG DGAQAAVKGA QAELMKVQAL EKVKGADINA EEAPKMVPKA
     VEDGIKVADL ELEEGLAEEK LKTVEEAAAP REGQGSSAVG FEVPQQDVIL PEY
//
DBGET integrated database retrieval system