ID HDAC4_HUMAN Reviewed; 1084 AA. AC P56524; E9PGB9; F5GX36; Q86YH7; Q9UND6; DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot. DT 22-SEP-2009, sequence version 3. DT 27-MAR-2024, entry version 228. DE RecName: Full=Histone deacetylase 4 {ECO:0000305|PubMed:10220385}; DE Short=HD4; DE EC=3.5.1.98 {ECO:0000269|PubMed:10220385, ECO:0000269|PubMed:10523670, ECO:0000269|PubMed:12032081}; GN Name=HDAC4 {ECO:0000312|HGNC:HGNC:14063}; Synonyms=KIAA0288; 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] (ISOFORM 1), AND CATALYTIC ACTIVITY. RC TISSUE=Leukemia; RX PubMed=10220385; DOI=10.1073/pnas.96.9.4868; RA Grozinger C.M., Hassig C.A., Schreiber S.L.; RT "Three proteins define a class of human histone deacetylases related to RT yeast Hda1p."; RL Proc. Natl. Acad. Sci. U.S.A. 96:4868-4873(1999). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=9179496; DOI=10.1093/dnares/4.1.53; RA Ohara O., Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., RA Nomura N.; RT "Construction and characterization of human brain cDNA libraries suitable RT for analysis of cDNA clones encoding relatively large proteins."; RL DNA Res. 4:53-59(1997). RN [3] RP SEQUENCE REVISION TO N-TERMINUS. RA Ohara O., Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., RA Nomura N.; RL Submitted (DEC-1999) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Testis; 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 [7] RP SUBCELLULAR LOCATION, AND INTERACTION WITH MEF2A. RX PubMed=10487761; DOI=10.1093/emboj/18.18.5099; RA Miska E.A., Karlsson C., Langley E., Nielsen S.J., Pines J., Kouzarides T.; RT "HDAC4 deacetylase associates with and represses the MEF2 transcription RT factor."; RL EMBO J. 18:5099-5107(1999). RN [8] RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH MEF2C AND MEF2D, AND RP MUTAGENESIS OF HIS-803. RX PubMed=10523670; DOI=10.1128/mcb.19.11.7816; RA Wang A.H., Bertos N.R., Vezmar M., Pelletier N., Crosato M., Heng H.H., RA Th'ng J., Han J., Yang X.-J.; RT "HDAC4, a human histone deacetylase related to yeast HDA1, is a RT transcriptional corepressor."; RL Mol. Cell. Biol. 19:7816-7827(1999). RN [9] RP PHOSPHORYLATION AT SER-246; SER-467 AND SER-632, MUTAGENESIS OF SER-246; RP SER-467 AND SER-632, AND INTERACTION WITH 14-3-3 PROTEINS. RX PubMed=10958686; DOI=10.1128/mcb.20.18.6904-6912.2000; RA Wang A.H., Kruhlak M.J., Wu J., Bertos N.R., Vezmar M., Posner B.I., RA Bazett-Jones D.P., Yang X.-J.; RT "Regulation of histone deacetylase 4 by binding of 14-3-3 proteins."; RL Mol. Cell. Biol. 20:6904-6912(2000). RN [10] RP SUBCELLULAR LOCATION, PHOSPHORYLATION, AND MUTAGENESIS OF SER-467 AND RP SER-632. RX PubMed=11470791; DOI=10.1074/jbc.m105086200; RA Zhao X., Ito A., Kane C.D., Liao T.-S., Bolger T.A., Lemrow S.M., RA Means A.R., Yao T.-P.; RT "The modular nature of histone deacetylase HDAC4 confers phosphorylation- RT dependent intracellular trafficking."; RL J. Biol. Chem. 276:35042-35048(2001). RN [11] RP NUCLEAR EXPORT SIGNAL, AND MUTAGENESIS OF VAL-1056 AND LEU-1062. RX PubMed=11509672; DOI=10.1128/mcb.21.18.6312-6321.2001; RA McKinsey T.A., Zhang C.-L., Olson E.N.; RT "Identification of a signal-responsive nuclear export sequence in class II RT histone deacetylases."; RL Mol. Cell. Biol. 21:6312-6321(2001). RN [12] RP INTERACTION WITH NR2C1. RX PubMed=11463856; DOI=10.1210/mend.15.8.0682; RA Franco P.J., Farooqui M., Seto E., Wei L.-N.; RT "The orphan nuclear receptor TR2 interacts directly with both class I and RT class II histone deacetylases."; RL Mol. Endocrinol. 15:1318-1328(2001). RN [13] RP CATALYTIC ACTIVITY, HOMODIMERIZATION, SUMOYLATION AT LYS-559, AND RP MUTAGENESIS OF LYS-559. RX PubMed=12032081; DOI=10.1093/emboj/21.11.2682; RA Kirsh O., Seeler J.-S., Pichler A., Gast A., Mueller S., Miska E., RA Mathieu M., Harel-Bellan A., Kouzarides T., Melchior F., Dejean A.; RT "The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 RT deacetylase."; RL EMBO J. 21:2682-2691(2002). RN [14] RP INTERACTION WITH KDM5B. RX PubMed=17373667; DOI=10.1002/ijc.22673; RA Barrett A., Santangelo S., Tan K., Catchpole S., Roberts K., RA Spencer-Dene B., Hall D., Scibetta A., Burchell J., Verdin E., Freemont P., RA Taylor-Papadimitriou J.; RT "Breast cancer associated transcriptional repressor PLU-1/JARID1B interacts RT directly with histone deacetylases."; RL Int. J. Cancer 121:265-275(2007). RN [15] RP PHOSPHORYLATION BY CAMK2D. RX PubMed=17179159; DOI=10.1074/jbc.m604281200; RA Little G.H., Bai Y., Williams T., Poizat C.; RT "Nuclear calcium/calmodulin-dependent protein kinase IIdelta preferentially RT transmits signals to histone deacetylase 4 in cardiac cells."; RL J. Biol. Chem. 282:7219-7231(2007). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-632 AND SER-633, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-350, 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 [18] RP INVOLVEMENT IN BDMR. RX PubMed=20691407; DOI=10.1016/j.ajhg.2010.07.011; RA Williams S.R., Aldred M.A., Der Kaloustian V.M., Halal F., Gowans G., RA McLeod D.R., Zondag S., Toriello H.V., Magenis R.E., Elsea S.H.; RT "Haploinsufficiency of HDAC4 causes brachydactyly mental retardation RT syndrome, with brachydactyly type E, developmental delays, and behavioral RT problems."; RL Am. J. Hum. Genet. 87:219-228(2010). RN [19] RP INTERACTION WITH MORC2. RX PubMed=20110259; DOI=10.1093/nar/gkq006; RA Shao Y., Li Y., Zhang J., Liu D., Liu F., Zhao Y., Shen T., Li F.; RT "Involvement of histone deacetylation in MORC2-mediated down-regulation of RT carbonic anhydrase IX."; RL Nucleic Acids Res. 38:2813-2824(2010). RN [20] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [21] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [22] RP INVOLVEMENT IN BDMR. RX PubMed=23188045; DOI=10.1038/ejhg.2012.240; RA Villavicencio-Lorini P., Klopocki E., Trimborn M., Koll R., Mundlos S., RA Horn D.; RT "Phenotypic variant of Brachydactyly-mental retardation syndrome in a RT family with an inherited interstitial 2q37.3 microdeletion including RT HDAC4."; RL Eur. J. Hum. Genet. 21:743-748(2013). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-632, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [24] RP FUNCTION, AND INTERACTION WITH EP300. RX PubMed=24413532; DOI=10.1158/0008-5472.can-13-2020; RA Kang H.J., Lee M.H., Kang H.L., Kim S.H., Ahn J.R., Na H., Na T.Y., RA Kim Y.N., Seong J.K., Lee M.O.; RT "Differential regulation of estrogen receptor alpha expression in breast RT cancer cells by metastasis-associated protein 1."; RL Cancer Res. 74:1484-1494(2014). RN [25] RP INVOLVEMENT IN BDMR. RX PubMed=24715439; DOI=10.1002/ajmg.a.36542; RA Wheeler P.G., Huang D., Dai Z.; RT "Haploinsufficiency of HDAC4 does not cause intellectual disability in all RT affected individuals."; RL Am. J. Med. Genet. A 164A:1826-1829(2014). RN [26] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-632, AND IDENTIFICATION BY RP 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 INTERACTION WITH CUL7 AND ANKRA2, AND MUTAGENESIS OF PRO-349 AND ILE-354. RX PubMed=25752541; DOI=10.1016/j.str.2015.02.001; RA Nie J., Xu C., Jin J., Aka J.A., Tempel W., Nguyen V., You L., Weist R., RA Min J., Pawson T., Yang X.J.; RT "Ankyrin repeats of ANKRA2 recognize a PxLPxL motif on the 3M syndrome RT protein CCDC8."; RL Structure 23:700-712(2015). RN [28] RP FUNCTION, AND INTERACTION WITH HSPA1A AND HSPA1B. RX PubMed=27708256; DOI=10.1038/ncomms12882; RA Seo J.H., Park J.H., Lee E.J., Vo T.T., Choi H., Kim J.Y., Jang J.K., RA Wee H.J., Lee H.S., Jang S.H., Park Z.Y., Jeong J., Lee K.J., Seok S.H., RA Park J.Y., Lee B.J., Lee M.N., Oh G.T., Kim K.W.; RT "ARD1-mediated Hsp70 acetylation balances stress-induced protein refolding RT and degradation."; RL Nat. Commun. 7:12882-12882(2016). RN [29] RP INTERACTION WITH ZNF638. RX PubMed=30487602; DOI=10.1038/s41586-018-0750-6; RA Zhu Y., Wang G.Z., Cingoez O., Goff S.P.; RT "NP220 mediates silencing of unintegrated retroviral DNA."; RL Nature 564:278-282(2018). RN [30] RP X-RAY CRYSTALLOGRAPHY (1.57 ANGSTROMS) OF 343-359 IN COMPLEX WITH ANKRA2, RP PHOSPHORYLATION AT SER-350, MOTIF, AND MUTAGENESIS OF LEU-345; TYR-346; RP THR-347; SER-348; PRO-349; SER-350; LEU-351; PRO-352; ASN-353; ILE-354; RP THR-355 AND LEU-356. RX PubMed=22649097; DOI=10.1126/scisignal.2002979; RA Xu C., Jin J., Bian C., Lam R., Tian R., Weist R., You L., Nie J., RA Bochkarev A., Tempel W., Tan C.S., Wasney G.A., Vedadi M., Gish G.D., RA Arrowsmith C.H., Pawson T., Yang X.J., Min J.; RT "Sequence-specific recognition of a PxLPxI/L motif by an ankyrin repeat RT tumbler lock."; RL Sci. Signal. 5:RA39-RA39(2012). RN [31] RP VARIANT [LARGE SCALE ANALYSIS] ARG-727. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [32] RP VARIANT ILE-754. RX PubMed=24169519; DOI=10.1038/ejhg.2013.243; RA Piton A., Poquet H., Redin C., Masurel A., Lauer J., Muller J., RA Thevenon J., Herenger Y., Chancenotte S., Bonnet M., Pinoit J.M., Huet F., RA Thauvin-Robinet C., Jaeger A.S., Le Gras S., Jost B., Gerard B., Peoc'h K., RA Launay J.M., Faivre L., Mandel J.L.; RT "20 ans apres: a second mutation in MAOA identified by targeted high- RT throughput sequencing in a family with altered behavior and cognition."; RL Eur. J. Hum. Genet. 22:776-783(2014). RN [33] RP VARIANTS NEDCHF LYS-244; GLY-247; ALA-248 AND LEU-248, INVOLVEMENT IN RP NEDCHF, CHARACTERIZATION OF VARIANTS NEDCHF LYS-244 AND GLY-247, AND RP INTERACTION WITH YWHAB. RX PubMed=33537682; DOI=10.1016/j.xhgg.2020.100015; RG DDD Study; RA Wakeling E., McEntagart M., Bruccoleri M., Shaw-Smith C., Stals K.L., RA Wakeling M., Barnicoat A., Beesley C., Hanson-Kahn A.K., Kukolich M., RA Stevenson D.A., Campeau P.M., Ellard S., Elsea S.H., Yang X.J., RA Caswell R.C.; RT "Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a RT novel intellectual disability syndrome."; RL HGG Adv. 2:100015-100015(2021). CC -!- FUNCTION: Responsible for the deacetylation of lysine residues on the CC N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone CC deacetylation gives a tag for epigenetic repression and plays an CC important role in transcriptional regulation, cell cycle progression CC and developmental events. Histone deacetylases act via the formation of CC large multiprotein complexes. Involved in muscle maturation via its CC interaction with the myocyte enhancer factors such as MEF2A, MEF2C and CC MEF2D. Involved in the MTA1-mediated epigenetic regulation of ESR1 CC expression in breast cancer. Deacetylates HSPA1A and HSPA1B at 'Lys-77' CC leading to their preferential binding to co-chaperone STUB1 CC (PubMed:27708256). {ECO:0000269|PubMed:10523670, CC ECO:0000269|PubMed:24413532, ECO:0000269|PubMed:27708256}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + N(6)-acetyl-L-lysyl-[histone] = acetate + L-lysyl- CC [histone]; Xref=Rhea:RHEA:58196, Rhea:RHEA-COMP:9845, Rhea:RHEA- CC COMP:11338, ChEBI:CHEBI:15377, ChEBI:CHEBI:29969, ChEBI:CHEBI:30089, CC ChEBI:CHEBI:61930; EC=3.5.1.98; CC Evidence={ECO:0000269|PubMed:10220385, ECO:0000269|PubMed:10523670, CC ECO:0000269|PubMed:12032081}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58197; CC Evidence={ECO:0000269|PubMed:10523670, ECO:0000269|PubMed:12032081}; CC -!- SUBUNIT: Homodimer. Homodimerization via its N-terminal domain CC (PubMed:12032081). Interacts with MEF2A (PubMed:10487761). Interacts CC with MEF2C and MEF2D (PubMed:10523670). Interacts with AHRR (By CC similarity). Interacts with NR2C1 (PubMed:11463856). Interacts with CC HDAC7 (By similarity). Interacts with a 14-3-3 chaperone proteins in a CC phosphorylation dependent manner (PubMed:10958686). Interacts with 14- CC 3-3 protein YWHAB (PubMed:33537682). Interacts with BTBD14B (By CC similarity). Interacts with KDM5B (PubMed:17373667). Interacts with CC MYOCD (By similarity). Interacts with MORC2 (PubMed:20110259). CC Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats). CC Interacts with CUL7 (as part of the 3M complex); negatively regulated CC by ANKRA2 (PubMed:25752541). Interacts with EP300 in the presence of CC TFAP2C (PubMed:24413532). Interacts with HSPA1A and HSPA1B leading to CC their deacetylation at 'Lys-77' (PubMed:27708256). Interacts with CC ZBTB7B; the interaction allows the recruitment of HDAC4 on CD8 loci for CC deacetylation and possible inhibition of CD8 genes expression (By CC similarity). Interacts with DHX36 (By similarity). Interacts with SIK3; CC this interaction leads to HDAC4 retention in the cytoplasm (By CC similarity). Interacts with ZNF638 (PubMed:30487602). CC {ECO:0000250|UniProtKB:Q6NZM9, ECO:0000250|UniProtKB:Q99P99, CC ECO:0000269|PubMed:10487761, ECO:0000269|PubMed:10523670, CC ECO:0000269|PubMed:10958686, ECO:0000269|PubMed:11463856, CC ECO:0000269|PubMed:17373667, ECO:0000269|PubMed:20110259, CC ECO:0000269|PubMed:22649097, ECO:0000269|PubMed:24413532, CC ECO:0000269|PubMed:25752541, ECO:0000269|PubMed:27708256, CC ECO:0000269|PubMed:30487602, ECO:0000269|PubMed:33537682}. CC -!- INTERACTION: CC P56524; Q9H9E1: ANKRA2; NbExp=3; IntAct=EBI-308629, EBI-10215533; CC P56524; P10275: AR; NbExp=4; IntAct=EBI-308629, EBI-608057; CC P56524; P15336: ATF2; NbExp=2; IntAct=EBI-308629, EBI-1170906; CC P56524; P41182: BCL6; NbExp=3; IntAct=EBI-308629, EBI-765407; CC P56524; Q9HCU9: BRMS1; NbExp=2; IntAct=EBI-308629, EBI-714781; CC P56524; Q96JN2-2: CCDC136; NbExp=3; IntAct=EBI-308629, EBI-10171416; CC P56524; Q01850: CDR2; NbExp=3; IntAct=EBI-308629, EBI-1181367; CC P56524; O95967: EFEMP2; NbExp=3; IntAct=EBI-308629, EBI-743414; CC P56524; Q08379: GOLGA2; NbExp=3; IntAct=EBI-308629, EBI-618309; CC P56524; P56524: HDAC4; NbExp=4; IntAct=EBI-308629, EBI-308629; CC P56524; Q15323: KRT31; NbExp=3; IntAct=EBI-308629, EBI-948001; CC P56524; O76015: KRT38; NbExp=3; IntAct=EBI-308629, EBI-1047263; CC P56524; Q6A162: KRT40; NbExp=3; IntAct=EBI-308629, EBI-10171697; CC P56524; O95751: LDOC1; NbExp=3; IntAct=EBI-308629, EBI-740738; CC P56524; A9UHW6: MIF4GD; NbExp=4; IntAct=EBI-308629, EBI-373498; CC P56524; Q5JR59: MTUS2; NbExp=3; IntAct=EBI-308629, EBI-742948; CC P56524; Q8ND90: PNMA1; NbExp=3; IntAct=EBI-308629, EBI-302345; CC P56524; Q6NUQ1: RINT1; NbExp=3; IntAct=EBI-308629, EBI-726876; CC P56524; Q13761: RUNX3; NbExp=9; IntAct=EBI-308629, EBI-925990; CC P56524; P31947: SFN; NbExp=8; IntAct=EBI-308629, EBI-476295; CC P56524; P63279: UBE2I; NbExp=3; IntAct=EBI-308629, EBI-80168; CC P56524; P31946: YWHAB; NbExp=5; IntAct=EBI-308629, EBI-359815; CC P56524; P62258: YWHAE; NbExp=8; IntAct=EBI-308629, EBI-356498; CC P56524; P61981: YWHAG; NbExp=11; IntAct=EBI-308629, EBI-359832; CC P56524; Q04917: YWHAH; NbExp=9; IntAct=EBI-308629, EBI-306940; CC P56524; P27348: YWHAQ; NbExp=5; IntAct=EBI-308629, EBI-359854; CC P56524; P63104: YWHAZ; NbExp=7; IntAct=EBI-308629, EBI-347088; CC P56524; O54946-2: Dnajb6; Xeno; NbExp=2; IntAct=EBI-308629, EBI-13941040; CC P56524; Q8AZK7: EBNA-LP; Xeno; NbExp=5; IntAct=EBI-308629, EBI-1185167; CC P56524; P08393: ICP0; Xeno; NbExp=3; IntAct=EBI-308629, EBI-6148881; CC P56524-2; Q8WXK1: ASB15; NbExp=3; IntAct=EBI-11953488, EBI-12809012; CC P56524-2; Q9BUH8: BEGAIN; NbExp=3; IntAct=EBI-11953488, EBI-742722; CC P56524-2; Q8TD16-2: BICD2; NbExp=3; IntAct=EBI-11953488, EBI-11975051; CC P56524-2; Q9H2G9: BLZF1; NbExp=3; IntAct=EBI-11953488, EBI-2548012; CC P56524-2; A2RRN7: CADPS; NbExp=3; IntAct=EBI-11953488, EBI-10179719; CC P56524-2; Q13137: CALCOCO2; NbExp=3; IntAct=EBI-11953488, EBI-739580; CC P56524-2; Q86Z20: CCDC125; NbExp=3; IntAct=EBI-11953488, EBI-11977221; CC P56524-2; O95273: CCNDBP1; NbExp=3; IntAct=EBI-11953488, EBI-748961; CC P56524-2; Q6NVV7: CDPF1; NbExp=3; IntAct=EBI-11953488, EBI-2802782; CC P56524-2; Q01850: CDR2; NbExp=3; IntAct=EBI-11953488, EBI-1181367; CC P56524-2; Q86X02: CDR2L; NbExp=3; IntAct=EBI-11953488, EBI-11063830; CC P56524-2; Q8NHQ1: CEP70; NbExp=3; IntAct=EBI-11953488, EBI-739624; CC P56524-2; Q8WWB3: DYDC1; NbExp=3; IntAct=EBI-11953488, EBI-740680; CC P56524-2; Q5JST6: EFHC2; NbExp=3; IntAct=EBI-11953488, EBI-2349927; CC P56524-2; O94868-3: FCHSD2; NbExp=3; IntAct=EBI-11953488, EBI-11958845; CC P56524-2; A1L4K1: FSD2; NbExp=3; IntAct=EBI-11953488, EBI-5661036; CC P56524-2; Q08379: GOLGA2; NbExp=3; IntAct=EBI-11953488, EBI-618309; CC P56524-2; A6NEM1: GOLGA6L9; NbExp=3; IntAct=EBI-11953488, EBI-5916454; CC P56524-2; Q4V328: GRIPAP1; NbExp=3; IntAct=EBI-11953488, EBI-717919; CC P56524-2; P54257: HAP1; NbExp=3; IntAct=EBI-11953488, EBI-712814; CC P56524-2; Q96ED9-2: HOOK2; NbExp=3; IntAct=EBI-11953488, EBI-10961706; CC P56524-2; O75031: HSF2BP; NbExp=3; IntAct=EBI-11953488, EBI-7116203; CC P56524-2; Q0VD86: INCA1; NbExp=3; IntAct=EBI-11953488, EBI-6509505; CC P56524-2; Q7Z3Y8: KRT27; NbExp=3; IntAct=EBI-11953488, EBI-3044087; CC P56524-2; Q15323: KRT31; NbExp=3; IntAct=EBI-11953488, EBI-948001; CC P56524-2; Q14525: KRT33B; NbExp=3; IntAct=EBI-11953488, EBI-1049638; CC P56524-2; O76011: KRT34; NbExp=3; IntAct=EBI-11953488, EBI-1047093; CC P56524-2; Q92764: KRT35; NbExp=3; IntAct=EBI-11953488, EBI-1058674; CC P56524-2; Q6A162: KRT40; NbExp=3; IntAct=EBI-11953488, EBI-10171697; CC P56524-2; O95751: LDOC1; NbExp=3; IntAct=EBI-11953488, EBI-740738; CC P56524-2; Q02078-5: MEF2A; NbExp=3; IntAct=EBI-11953488, EBI-12232917; CC P56524-2; Q02080: MEF2B; NbExp=3; IntAct=EBI-11953488, EBI-6427785; CC P56524-2; Q06413: MEF2C; NbExp=5; IntAct=EBI-11953488, EBI-2684075; CC P56524-2; Q9UJV3-2: MID2; NbExp=3; IntAct=EBI-11953488, EBI-10172526; CC P56524-2; Q5JR59-3: MTUS2; NbExp=3; IntAct=EBI-11953488, EBI-11522433; CC P56524-2; Q8NI38: NFKBID; NbExp=3; IntAct=EBI-11953488, EBI-10271199; CC P56524-2; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-11953488, EBI-79165; CC P56524-2; Q9Y2D8: SSX2IP; NbExp=3; IntAct=EBI-11953488, EBI-2212028; CC P56524-2; Q9UBB9: TFIP11; NbExp=3; IntAct=EBI-11953488, EBI-1105213; CC P56524-2; Q08117-2: TLE5; NbExp=3; IntAct=EBI-11953488, EBI-11741437; CC P56524-2; Q96RU7: TRIB3; NbExp=3; IntAct=EBI-11953488, EBI-492476; CC P56524-2; P14373: TRIM27; NbExp=3; IntAct=EBI-11953488, EBI-719493; CC P56524-2; Q9BZW7: TSGA10; NbExp=3; IntAct=EBI-11953488, EBI-744794; CC P56524-2; Q8N1B4: VPS52; NbExp=3; IntAct=EBI-11953488, EBI-2799833; CC P56524-2; P62258: YWHAE; NbExp=3; IntAct=EBI-11953488, EBI-356498; CC P56524-2; Q9H0C1: ZMYND12; NbExp=3; IntAct=EBI-11953488, EBI-12030590; CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Note=Shuttles between the CC nucleus and the cytoplasm. Upon muscle cells differentiation, it CC accumulates in the nuclei of myotubes, suggesting a positive role of CC nuclear HDAC4 in muscle differentiation. The export to cytoplasm CC depends on the interaction with a 14-3-3 chaperone protein and is due CC to its phosphorylation at Ser-246, Ser-467 and Ser-632 by CaMK4 and CC SIK1. The nuclear localization probably depends on sumoylation. CC Interaction with SIK3 leads to HDAC4 retention in the cytoplasm (By CC similarity). {ECO:0000250|UniProtKB:Q6NZM9}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P56524-1; Sequence=Displayed; CC Name=2; CC IsoId=P56524-2; Sequence=VSP_057290, VSP_057291; CC -!- TISSUE SPECIFICITY: Ubiquitous. CC -!- DOMAIN: The nuclear export sequence mediates the shuttling between the CC nucleus and the cytoplasm. CC -!- DOMAIN: The PxLPxI/L motif mediates interaction with ankyrin repeats of CC ANKRA2. {ECO:0000269|PubMed:22649097}. CC -!- PTM: Phosphorylated by CaMK4 at Ser-246, Ser-467 and Ser-632. CC Phosphorylation at other residues by CaMK2D is required for the CC interaction with 14-3-3. Phosphorylation at Ser-350, within the CC PxLPxI/L motif, impairs the binding of ANKRA2 but generates a high- CC affinity docking site for 14-3-3. {ECO:0000269|PubMed:10958686, CC ECO:0000269|PubMed:22649097}. CC -!- PTM: Sumoylation on Lys-559 is promoted by the E3 SUMO-protein ligase CC RANBP2, and prevented by phosphorylation by CaMK4. CC {ECO:0000269|PubMed:12032081}. CC -!- DISEASE: Note=HDAC4 point mutations and chromosomal microdeletions CC encompassing this gene have been found in patients with brachydactyly CC and intellectual disability syndrome (PubMed:20691407, PubMed:24715439, CC PubMed:23188045). However, HDAC4 haploinsufficiency is not fully CC penetrant and multiple genes may contribute to manifestation of the CC full phenotypic spectrum (PubMed:24715439, PubMed:23188045). CC {ECO:0000269|PubMed:20691407, ECO:0000269|PubMed:23188045, CC ECO:0000269|PubMed:24715439}. CC -!- DISEASE: Neurodevelopmental disorder with central hypotonia and CC dysmorphic facies (NEDCHF) [MIM:619797]: An autosomal dominant disease CC characterized by global developmental delay, impaired intellectual CC development, seizures, distinctive facial features, scoliosis, delayed CC closure of the anterior fontanel, and non-specific brain abnormalities. CC {ECO:0000269|PubMed:33537682}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the histone deacetylase family. HD type 2 CC subfamily. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAA22957.2; Type=Erroneous initiation; 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; AF132607; AAD29046.1; -; mRNA. DR EMBL; AB006626; BAA22957.2; ALT_INIT; mRNA. DR EMBL; AC017028; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC062017; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; KF510800; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; KF510801; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471063; EAW71165.1; -; Genomic_DNA. DR EMBL; BC039904; AAH39904.1; -; mRNA. DR CCDS; CCDS2529.1; -. [P56524-1] DR RefSeq; NP_006028.2; NM_006037.3. [P56524-1] DR PDB; 2H8N; X-ray; 2.60 A; A/B/C/D=62-153. DR PDB; 2O94; X-ray; 3.00 A; A/B/C/D=62-153. DR PDB; 2VQJ; X-ray; 2.10 A; A=648-1057. DR PDB; 2VQM; X-ray; 1.80 A; A=648-1057. DR PDB; 2VQO; X-ray; 2.15 A; A/B=648-1057. DR PDB; 2VQQ; X-ray; 1.90 A; A/B=648-1057. DR PDB; 2VQV; X-ray; 3.30 A; A/B=648-1057. DR PDB; 2VQW; X-ray; 3.00 A; G=648-1057. DR PDB; 3UXG; X-ray; 1.85 A; B=343-359. DR PDB; 3UZD; X-ray; 1.86 A; B=343-359. DR PDB; 3V31; X-ray; 1.57 A; B=343-359. DR PDB; 4CBT; X-ray; 3.03 A; A/B/C=648-1033. DR PDB; 4CBY; X-ray; 2.72 A; A/B/C/D=648-1033. DR PDB; 5A2S; X-ray; 2.65 A; A/B=648-1033. DR PDB; 5ZOO; X-ray; 1.85 A; G=652-1053. DR PDB; 5ZOP; X-ray; 2.70 A; G=652-1050. DR PDB; 6FYZ; X-ray; 2.15 A; A/B/C=648-1033. DR PDB; 7XUZ; X-ray; 3.59 A; A/B=62-192. DR PDBsum; 2H8N; -. DR PDBsum; 2O94; -. DR PDBsum; 2VQJ; -. DR PDBsum; 2VQM; -. DR PDBsum; 2VQO; -. DR PDBsum; 2VQQ; -. DR PDBsum; 2VQV; -. DR PDBsum; 2VQW; -. DR PDBsum; 3UXG; -. DR PDBsum; 3UZD; -. DR PDBsum; 3V31; -. DR PDBsum; 4CBT; -. DR PDBsum; 4CBY; -. DR PDBsum; 5A2S; -. DR PDBsum; 5ZOO; -. DR PDBsum; 5ZOP; -. DR PDBsum; 6FYZ; -. DR PDBsum; 7XUZ; -. DR AlphaFoldDB; P56524; -. DR SMR; P56524; -. DR BioGRID; 115106; 403. DR CORUM; P56524; -. DR DIP; DIP-34565N; -. DR ELM; P56524; -. DR IntAct; P56524; 93. DR MINT; P56524; -. DR STRING; 9606.ENSP00000264606; -. DR BindingDB; P56524; -. DR ChEMBL; CHEMBL3524; -. DR DrugBank; DB08613; 2,2,2-TRIFLUORO-1-{5-[(3-PHENYL-5,6-DIHYDROIMIDAZO[1,2-A]PYRAZIN-7(8H)-YL)CARBONYL]THIOPHEN-2-YL}ETHANE-1,1-DIOL. DR DrugBank; DB12565; Abexinostat. DR DrugBank; DB05015; Belinostat. DR DrugBank; DB01262; Decitabine. DR DrugBank; DB11841; Entinostat. DR DrugBank; DB12645; Givinostat. DR DrugBank; DB07879; N-hydroxy-5-[(3-phenyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)carbonyl]thiophene-2-carboxamide. DR DrugBank; DB06603; Panobinostat. DR DrugBank; DB06819; Phenylbutyric acid. DR DrugBank; DB03766; Propanoic acid. DR DrugBank; DB12847; Pyroxamide. DR DrugBank; DB06176; Romidepsin. DR DrugBank; DB00313; Valproic acid. DR DrugBank; DB02546; Vorinostat. DR DrugBank; DB01593; Zinc. DR DrugBank; DB14487; Zinc acetate. DR DrugBank; DB14533; Zinc chloride. DR DrugBank; DB14548; Zinc sulfate, unspecified form. DR DrugCentral; P56524; -. DR GuidetoPHARMACOLOGY; 2659; -. DR GlyCosmos; P56524; 1 site, 1 glycan. DR GlyGen; P56524; 3 sites, 1 O-linked glycan (3 sites). DR iPTMnet; P56524; -. DR MetOSite; P56524; -. DR PhosphoSitePlus; P56524; -. DR BioMuta; HDAC4; -. DR DMDM; 259016348; -. DR EPD; P56524; -. DR jPOST; P56524; -. DR MassIVE; P56524; -. DR MaxQB; P56524; -. DR PaxDb; 9606-ENSP00000264606; -. DR PeptideAtlas; P56524; -. DR ProteomicsDB; 24301; -. DR ProteomicsDB; 56920; -. [P56524-1] DR ProteomicsDB; 70417; -. DR Pumba; P56524; -. DR ABCD; P56524; 1 sequenced antibody. DR Antibodypedia; 3835; 1398 antibodies from 51 providers. DR DNASU; 9759; -. DR Ensembl; ENST00000345617.7; ENSP00000264606.3; ENSG00000068024.18. [P56524-1] DR GeneID; 9759; -. DR KEGG; hsa:9759; -. DR UCSC; uc002vyk.4; human. [P56524-1] DR AGR; HGNC:14063; -. DR CTD; 9759; -. DR DisGeNET; 9759; -. DR GeneCards; HDAC4; -. DR HGNC; HGNC:14063; HDAC4. DR HPA; ENSG00000068024; Tissue enhanced (skeletal). DR MalaCards; HDAC4; -. DR MIM; 605314; gene. DR MIM; 619797; phenotype. DR neXtProt; NX_P56524; -. DR OpenTargets; ENSG00000068024; -. DR Orphanet; 1001; 2q37 microdeletion syndrome. DR PharmGKB; PA29229; -. DR VEuPathDB; HostDB:ENSG00000068024; -. DR eggNOG; KOG1343; Eukaryota. DR GeneTree; ENSGT00940000157440; -. DR HOGENOM; CLU_006530_2_0_1; -. DR InParanoid; P56524; -. DR OrthoDB; 124800at2759; -. DR PhylomeDB; P56524; -. DR TreeFam; TF106174; -. DR BRENDA; 3.5.1.98; 2681. DR PathwayCommons; P56524; -. DR Reactome; R-HSA-2122947; NOTCH1 Intracellular Domain Regulates Transcription. DR Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants. DR Reactome; R-HSA-2894862; Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants. DR Reactome; R-HSA-350054; Notch-HLH transcription pathway. DR Reactome; R-HSA-4090294; SUMOylation of intracellular receptors. DR Reactome; R-HSA-4551638; SUMOylation of chromatin organization proteins. DR Reactome; R-HSA-8941284; RUNX2 regulates chondrocyte maturation. DR Reactome; R-HSA-8951936; RUNX3 regulates p14-ARF. DR SignaLink; P56524; -. DR SIGNOR; P56524; -. DR BioGRID-ORCS; 9759; 21 hits in 1170 CRISPR screens. DR ChiTaRS; HDAC4; human. DR EvolutionaryTrace; P56524; -. DR GeneWiki; HDAC4; -. DR GenomeRNAi; 9759; -. DR Pharos; P56524; Tclin. DR PRO; PR:P56524; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; P56524; Protein. DR Bgee; ENSG00000068024; Expressed in sural nerve and 199 other cell types or tissues. DR ExpressionAtlas; P56524; baseline and differential. DR GO; GO:0000785; C:chromatin; IDA:UniProt. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0000118; C:histone deacetylase complex; IDA:BHF-UCL. DR GO; GO:0016607; C:nuclear speck; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0017053; C:transcription repressor complex; IDA:BHF-UCL. DR GO; GO:0140297; F:DNA-binding transcription factor binding; IPI:BHF-UCL. DR GO; GO:0004407; F:histone deacetylase activity; IDA:MGI. DR GO; GO:0042826; F:histone deacetylase binding; IPI:BHF-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0060090; F:molecular adaptor activity; IDA:UniProt. DR GO; GO:0030955; F:potassium ion binding; IDA:BHF-UCL. DR GO; GO:0033558; F:protein lysine deacetylase activity; IDA:BHF-UCL. DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:UniProtKB. DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0019789; F:SUMO transferase activity; EXP:Reactome. DR GO; GO:0008270; F:zinc ion binding; IDA:BHF-UCL. DR GO; GO:0042113; P:B cell activation; TAS:UniProtKB. DR GO; GO:0030183; P:B cell differentiation; TAS:UniProtKB. DR GO; GO:0014898; P:cardiac muscle hypertrophy in response to stress; TAS:BHF-UCL. DR GO; GO:0006338; P:chromatin remodeling; IDA:BHF-UCL. DR GO; GO:0006954; P:inflammatory response; TAS:UniProtKB. DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; IMP:BHF-UCL. DR GO; GO:0045814; P:negative regulation of gene expression, epigenetic; IDA:BHF-UCL. DR GO; GO:0045820; P:negative regulation of glycolytic process; ISS:BHF-UCL. DR GO; GO:0010832; P:negative regulation of myotube differentiation; IMP:BHF-UCL. DR GO; GO:0010944; P:negative regulation of transcription by competitive promoter binding; IMP:BHF-UCL. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:BHF-UCL. DR GO; GO:0007399; P:nervous system development; TAS:UniProtKB. DR GO; GO:0034983; P:peptidyl-lysine deacetylation; IDA:BHF-UCL. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:BHF-UCL. DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; IMP:BHF-UCL. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; ISS:BHF-UCL. DR GO; GO:0033235; P:positive regulation of protein sumoylation; IDA:UniProtKB. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:BHF-UCL. DR GO; GO:0006476; P:protein deacetylation; IDA:UniProtKB. DR GO; GO:0016925; P:protein sumoylation; TAS:Reactome. DR GO; GO:0043393; P:regulation of protein binding; IMP:BHF-UCL. DR GO; GO:0014894; P:response to denervation involved in regulation of muscle adaptation; ISS:BHF-UCL. DR GO; GO:0070555; P:response to interleukin-1; IMP:BHF-UCL. DR GO; GO:0060337; P:type I interferon-mediated signaling pathway; IDA:UniProt. DR CDD; cd10162; ClassIIa_HDAC4_Gln-rich-N; 1. DR CDD; cd10006; HDAC4; 1. DR Gene3D; 6.10.250.1550; -; 1. DR Gene3D; 3.40.800.20; Histone deacetylase domain; 1. DR IDEAL; IID00457; -. DR InterPro; IPR046949; HDAC4/5/7/9. DR InterPro; IPR000286; His_deacetylse. DR InterPro; IPR023801; His_deacetylse_dom. DR InterPro; IPR037138; His_deacetylse_dom_sf. DR InterPro; IPR024643; Hist_deacetylase_Gln_rich_N. DR InterPro; IPR023696; Ureohydrolase_dom_sf. DR PANTHER; PTHR45364:SF11; HISTONE DEACETYLASE; 1. DR PANTHER; PTHR45364; HISTONE DEACETYLASE 9-RELATED; 1. DR Pfam; PF12203; HDAC4_Gln; 1. DR Pfam; PF00850; Hist_deacetyl; 1. DR PIRSF; PIRSF037911; HDAC_II_euk; 1. DR PRINTS; PR01270; HDASUPER. DR SUPFAM; SSF52768; Arginase/deacetylase; 1. DR Genevisible; P56524; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Chromatin regulator; Coiled coil; KW Cytoplasm; Disease variant; Epilepsy; Hydrolase; Intellectual disability; KW Isopeptide bond; Metal-binding; Nucleus; Phosphoprotein; KW Reference proteome; Repressor; Transcription; Transcription regulation; KW Ubl conjugation; Zinc. FT CHAIN 1..1084 FT /note="Histone deacetylase 4" FT /id="PRO_0000114699" FT REGION 118..313 FT /note="Interaction with MEF2A" FT /evidence="ECO:0000269|PubMed:10487761" FT REGION 133..166 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 206..226 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 240..315 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 509..531 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 548..585 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 626..646 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 655..1084 FT /note="Histone deacetylase" FT REGION 1061..1084 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 67..177 FT /evidence="ECO:0000255" FT MOTIF 349..354 FT /note="PxLPxI/L motif; mediates interaction with ANKRA2 and FT 14-3-3 proteins" FT /evidence="ECO:0000269|PubMed:22649097" FT MOTIF 1051..1084 FT /note="Nuclear export signal" FT /evidence="ECO:0000250" FT COMPBIAS 240..279 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 291..313 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 516..531 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1068..1084 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 803 FT /evidence="ECO:0000250" FT BINDING 667 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250" FT BINDING 669 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250" FT BINDING 675 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250" FT BINDING 751 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000250" FT MOD_RES 210 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q6NZM9" FT MOD_RES 246 FT /note="Phosphoserine; by CaMK4 and SIK1" FT /evidence="ECO:0000269|PubMed:10958686" FT MOD_RES 350 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:22649097, FT ECO:0007744|PubMed:19690332" FT MOD_RES 467 FT /note="Phosphoserine; by CaMK4 and SIK1" FT /evidence="ECO:0000269|PubMed:10958686" FT MOD_RES 565 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q6NZM9" FT MOD_RES 632 FT /note="Phosphoserine; by CaMK4" FT /evidence="ECO:0000269|PubMed:10958686, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 633 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT CROSSLNK 559 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO)" FT /evidence="ECO:0000269|PubMed:12032081" FT VAR_SEQ 1..117 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057290" FT VAR_SEQ 431 FT /note="T -> TDWYLS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057291" FT VARIANT 244 FT /note="T -> K (in NEDCHF; decreased interaction with FT YWHAB)" FT /evidence="ECO:0000269|PubMed:33537682" FT /id="VAR_087034" FT VARIANT 247 FT /note="E -> G (in NEDCHF; decreased interaction with FT YWHAB)" FT /evidence="ECO:0000269|PubMed:33537682" FT /id="VAR_087035" FT VARIANT 248 FT /note="P -> A (in NEDCHF)" FT /evidence="ECO:0000269|PubMed:33537682" FT /id="VAR_087036" FT VARIANT 248 FT /note="P -> L (in NEDCHF)" FT /evidence="ECO:0000269|PubMed:33537682" FT /id="VAR_087037" FT VARIANT 727 FT /note="P -> R (in a breast cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036042" FT VARIANT 754 FT /note="V -> I (in dbSNP:rs151043798)" FT /evidence="ECO:0000269|PubMed:24169519" FT /id="VAR_071965" FT MUTAGEN 246 FT /note="S->A: Reduces phosphorylation and its subsequent FT nuclear export." FT /evidence="ECO:0000269|PubMed:10958686" FT MUTAGEN 345 FT /note="L->A: No effect on interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097" FT MUTAGEN 346 FT /note="Y->A: No effect on interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097" FT MUTAGEN 347 FT /note="T->A: No effect on interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097" FT MUTAGEN 348 FT /note="S->A: No effect on interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097" FT MUTAGEN 349 FT /note="P->A: May affect interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097, FT ECO:0000269|PubMed:25752541" FT MUTAGEN 349 FT /note="P->G: Decreased interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097" FT MUTAGEN 350 FT /note="S->A: No effect on interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097" FT MUTAGEN 351 FT /note="L->A,G: Loss of interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097" FT MUTAGEN 352 FT /note="P->A: Loss of interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097" FT MUTAGEN 353 FT /note="N->A: No effect on interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097" FT MUTAGEN 354 FT /note="I->A: May affect interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097, FT ECO:0000269|PubMed:25752541" FT MUTAGEN 354 FT /note="I->G: Loss of interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097" FT MUTAGEN 355 FT /note="T->A: No effect on interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097" FT MUTAGEN 356 FT /note="L->A: No effect on interaction with ANKRA2." FT /evidence="ECO:0000269|PubMed:22649097" FT MUTAGEN 467 FT /note="S->A: Reduces phosphorylation and its subsequent FT nuclear export." FT /evidence="ECO:0000269|PubMed:10958686, FT ECO:0000269|PubMed:11470791" FT MUTAGEN 559 FT /note="K->R: Abolishes sumoylation and reduces the histone FT deacetylase activity." FT /evidence="ECO:0000269|PubMed:12032081" FT MUTAGEN 632 FT /note="S->A: Reduces phosphorylation and its subsequent FT nuclear export." FT /evidence="ECO:0000269|PubMed:10958686, FT ECO:0000269|PubMed:11470791" FT MUTAGEN 803 FT /note="H->L: Abolishes histone deacetylase activity." FT /evidence="ECO:0000269|PubMed:10523670" FT MUTAGEN 1056 FT /note="V->A: Reduces CaMK-dependent nuclear export." FT /evidence="ECO:0000269|PubMed:11509672" FT MUTAGEN 1062 FT /note="L->A: Reduces CaMK-dependent nuclear export." FT /evidence="ECO:0000269|PubMed:11509672" FT CONFLICT 373 FT /note="A -> T (in Ref. 1; AAD29046 and 2; BAA22957)" FT /evidence="ECO:0000305" FT HELIX 64..112 FT /evidence="ECO:0007829|PDB:2H8N" FT HELIX 115..121 FT /evidence="ECO:0007829|PDB:2H8N" FT TURN 122..125 FT /evidence="ECO:0007829|PDB:2H8N" FT HELIX 126..128 FT /evidence="ECO:0007829|PDB:2H8N" FT TURN 354..357 FT /evidence="ECO:0007829|PDB:3UXG" FT STRAND 652..657 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 660..662 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 672..674 FT /evidence="ECO:0007829|PDB:5ZOO" FT HELIX 681..691 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 694..697 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 698..701 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 708..711 FT /evidence="ECO:0007829|PDB:2VQM" FT TURN 712..714 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 717..724 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 727..730 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 737..745 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 746..748 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 754..756 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 762..786 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 789..795 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 813..815 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 817..828 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 834..838 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 840..842 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 845..851 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 857..864 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 866..868 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 870..872 FT /evidence="ECO:0007829|PDB:6FYZ" FT HELIX 883..885 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 889..894 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 898..900 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 904..913 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 915..922 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 925..931 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 936..938 FT /evidence="ECO:0007829|PDB:2VQM" FT TURN 940..943 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 950..961 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 964..966 FT /evidence="ECO:0007829|PDB:2VQM" FT STRAND 968..972 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 978..992 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 1002..1006 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 1011..1025 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 1029..1031 FT /evidence="ECO:0007829|PDB:2VQM" FT HELIX 1042..1047 FT /evidence="ECO:0007829|PDB:2VQM" SQ SEQUENCE 1084 AA; 119040 MW; BB7FD37652D12398 CRC64; MSSQSHPDGL SGRDQPVELL NPARVNHMPS TVDVATALPL QVAPSAVPMD LRLDHQFSLP VAEPALREQQ LQQELLALKQ KQQIQRQILI AEFQRQHEQL SRQHEAQLHE HIKQQQEMLA MKHQQELLEH QRKLERHRQE QELEKQHREQ KLQQLKNKEK GKESAVASTE VKMKLQEFVL NKKKALAHRN LNHCISSDPR YWYGKTQHSS LDQSSPPQSG VSTSYNHPVL GMYDAKDDFP LRKTASEPNL KLRSRLKQKV AERRSSPLLR RKDGPVVTAL KKRPLDVTDS ACSSAPGSGP SSPNNSSGSV SAENGIAPAV PSIPAETSLA HRLVAREGSA APLPLYTSPS LPNITLGLPA TGPSAGTAGQ QDAERLTLPA LQQRLSLFPG THLTPYLSTS PLERDGGAAH SPLLQHMVLL EQPPAQAPLV TGLGALPLHA QSLVGADRVS PSIHKLRQHR PLGRTQSAPL PQNAQALQHL VIQQQHQQFL EKHKQQFQQQ QLQMNKIIPK PSEPARQPES HPEETEEELR EHQALLDEPY LDRLPGQKEA HAQAGVQVKQ EPIESDEEEA EPPREVEPGQ RQPSEQELLF RQQALLLEQQ RIHQLRNYQA SMEAAGIPVS FGGHRPLSRA QSSPASATFP VSVQEPPTKP RFTTGLVYDT LMLKHQCTCG SSSSHPEHAG RIQSIWSRLQ ETGLRGKCEC IRGRKATLEE LQTVHSEAHT LLYGTNPLNR QKLDSKKLLG SLASVFVRLP CGGVGVDSDT IWNEVHSAGA ARLAVGCVVE LVFKVATGEL KNGFAVVRPP GHHAEESTPM GFCYFNSVAV AAKLLQQRLS VSKILIVDWD VHHGNGTQQA FYSDPSVLYM SLHRYDDGNF FPGSGAPDEV GTGPGVGFNV NMAFTGGLDP PMGDAEYLAA FRTVVMPIAS EFAPDVVLVS SGFDAVEGHP TPLGGYNLSA RCFGYLTKQL MGLAGGRIVL ALEGGHDLTA ICDASEACVS ALLGNELDPL PEKVLQQRPN ANAVRSMEKV MEIHSKYWRC LQRTTSTAGR SLIEAQTCEN EEAETVTAMA SLSVGVKPAE KRPDEEPMEE EPPL //