KCC4_HUMAN
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 03-AUG-2022, entry version 198.
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; DOI=10.1016/s0021-9258(20)80693-0;
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; DOI=10.1016/s0021-9258(19)61953-8;
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};
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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 AlphaFoldDB; Q16566; -.
DR SMR; Q16566; -.
DR BioGRID; 107264; 26.
DR DIP; DIP-41997N; -.
DR IntAct; Q16566; 30.
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; 642 antibodies from 42 providers.
DR DNASU; 814; -.
DR Ensembl; ENST00000282356.9; ENSP00000282356.4; ENSG00000152495.11.
DR Ensembl; ENST00000512453.5; ENSP00000422634.1; ENSG00000152495.11.
DR GeneID; 814; -.
DR KEGG; hsa:814; -.
DR MANE-Select; ENST00000282356.9; ENSP00000282356.4; NM_001744.6; NP_001735.1.
DR UCSC; uc003kpf.4; human.
DR CTD; 814; -.
DR DisGeNET; 814; -.
DR GeneCards; CAMK4; -.
DR HGNC; HGNC:1464; CAMK4.
DR HPA; ENSG00000152495; Group enriched (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; TKMVPEA; -.
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; 5 hits in 1104 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 cerebellar vermis and 138 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: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 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 52..60
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 75
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
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
