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 27-MAR-2024, entry version 207. 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}; 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 AlphaFoldDB; Q16566; -. DR SMR; Q16566; -. DR BioGRID; 107264; 52. 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 GlyCosmos; Q16566; 7 sites, 1 glycan. DR GlyGen; Q16566; 7 sites, 1 O-linked glycan (7 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; 9606-ENSP00000282356; -. DR PeptideAtlas; Q16566; -. DR ProteomicsDB; 60921; -. DR Pumba; Q16566; -. DR Antibodypedia; 2084; 721 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 AGR; HGNC:1464; -. 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; 1121238at2759; -. 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; 8 hits in 1186 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 140 other cell types or tissues. DR ExpressionAtlas; Q16566; baseline and differential. 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:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IBA:GO_Central. 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:0045893; P:positive regulation of DNA-templated transcription; IDA:UniProtKB. 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 CDD; cd14085; STKc_CaMKIV; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. 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 PANTHER; PTHR24347:SF391; CALCIUM_CALMODULIN DEPENDENT PROTEIN KINASE IV; 1. DR PANTHER; PTHR24347; SERINE/THREONINE-PROTEIN KINASE; 1. DR Pfam; PF00069; Pkinase; 1. DR SMART; SM00220; S_TKc; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1. DR Genevisible; Q16566; HS. 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 //