Q6NZM9 (HDAC4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Histone deacetylase 4
Short name=HD4
EC=3.5.1.98

Gene names

Name:

Hdac4

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	1076 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D By similarity.
Catalytic activity	Hydrolysis of an N(6)-acetyl-lysine residue of a histone to yield a deacetylated histone.
Subunit structure	Interacts with HDAC7. Homodimer. Homodimerization via its N-terminal domain. Interacts with MEF2C and NR2C1. Interacts with a 14-3-3 chaperone protein in a phosphorylation dependent manner. Interacts with BTBD14B. Interacts with KDM5B. Interacts with ANKRA2 By similarity. Interacts with AHRR. Interacts with MYOCD. Ref.3 Ref.4
Subcellular location	Nucleus. Cytoplasm. Note: Shuttles between the nucleus and the cytoplasm. Upon muscle cells differentiation, it accumulates in the nuclei of myotubes, suggesting a positive role of nuclear HDAC4 in muscle differentiation. The export to cytoplasm depends on the interaction with a 14-3-3 chaperone protein and is due to its phosphorylation at Ser-245, Ser-465 and Ser-629 by CaMK4 and SIK1. The nuclear localization probably depends on sumoylation By similarity.
Domain	The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm By similarity.
Post-translational modification	Phosphorylated by CaMK4 at Ser-245, Ser-465 and Ser-629. Phosphorylation at other residues by CaMK2D is required for the interaction with 14-3-3. Phosphorylation at Ser-349 impairs the binding of ANKRA2 but generates a high-affinity docking site for 14-3-3 By similarity. Ref.5 Ref.6 Sumoylation on Lys-556 is promoted by the E3 SUMO-protein ligase RANBP2, and prevented by phosphorylation by CaMK4.
Sequence similarities	Belongs to the histone deacetylase family. HD type 2 subfamily.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing
Domain	Coiled coil
Ligand	Metal-binding Zinc
Molecular function	Chromatin regulator Hydrolase Repressor
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	chromatin remodeling Inferred from electronic annotation. Source: Compara negative regulation of cell proliferation Inferred from direct assay PubMed 15537544. Source: MGI negative regulation of glycolysis Inferred from mutant phenotype PubMed 19109424. Source: BHF-UCL negative regulation of myotube differentiation Inferred from electronic annotation. Source: Compara negative regulation of osteoblast differentiation Inferred from mutant phenotype PubMed 15990875. Source: MGI negative regulation of sequence-specific DNA binding transcription factor activity Inferred from electronic annotation. Source: Compara negative regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 17873280. Source: MGI osteoblast development Inferred from mutant phenotype PubMed 15990875. Source: MGI peptidyl-lysine deacetylation Inferred from electronic annotation. Source: Compara positive regulation of cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of protein sumoylation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of sequence-specific DNA binding transcription factor activity Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from mutant phenotype PubMed 19109424. Source: BHF-UCL regulation of cardiac muscle contraction by calcium ion signaling Inferred from mutant phenotype PubMed 18250163. Source: MGI regulation of protein binding Inferred from electronic annotation. Source: Compara regulation of skeletal muscle fiber development Inferred from genetic interaction PubMed 17786239. Source: MGI response to denervation involved in regulation of muscle adaptation Inferred from mutant phenotype PubMed 19109424. Source: BHF-UCL response to drug Inferred from electronic annotation. Source: Compara response to interleukin-1 Inferred from electronic annotation. Source: Compara skeletal system development Inferred from mutant phenotype PubMed 15537544. Source: MGI transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	A band Inferred from electronic annotation. Source: Compara Z disc Inferred from electronic annotation. Source: Compara actomyosin Inferred from direct assay PubMed 18250163. Source: MGI cytosol Inferred from direct assay PubMed 17761942. Source: MGI histone deacetylase complex Inferred from electronic annotation. Source: Compara neuromuscular junction Inferred from direct assay PubMed 17873280. Source: MGI nucleus Inferred from mutant phenotype PubMed 19109424. Source: BHF-UCL transcriptional repressor complex Inferred from electronic annotation. Source: Compara
Molecular_function	DNA binding Inferred from direct assay PubMed 16260608. Source: MGI NAD-dependent histone deacetylase activity (H3-K14 specific) Inferred from electronic annotation. Source: EC NAD-dependent histone deacetylase activity (H3-K18 specific) Inferred from electronic annotation. Source: EC NAD-dependent histone deacetylase activity (H3-K9 specific) Inferred from electronic annotation. Source: EC NAD-dependent histone deacetylase activity (H4-K16 specific) Inferred from electronic annotation. Source: EC potassium ion binding Inferred from electronic annotation. Source: Compara protein deacetylase activity Inferred from direct assay PubMed 18250163. Source: MGI sequence-specific DNA binding Inferred from electronic annotation. Source: Compara transcription corepressor activity Inferred from genetic interaction PubMed 15990875. Source: MGI transcription regulatory region DNA binding Inferred from electronic annotation. Source: Compara zinc ion binding Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Runx2	Q08775	3	EBI-646397,EBI-903354

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q6NZM9-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q6NZM9-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-171: Missing.
     732-732: S → SKKLLG

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1076	1076	Histone deacetylase 4		PRO_0000281033
Regions
	Region	117 – 312	196	Interaction with MEF2A By similarity
	Region	652 – 1076	425	Histone deacetylase By similarity
	Coiled coil	66 – 169	104	Potential
	Motif	1043 – 1076	34	Nuclear export signal By similarity
	Compositional bias	464 – 499	36	Gln-rich
	Compositional bias	561 – 568	8	Poly-Glu
Sites
	Active site	795	1	By similarity
	Metal binding	664	1	Zinc By similarity
	Metal binding	666	1	Zinc By similarity
	Metal binding	672	1	Zinc By similarity
	Metal binding	743	1	Zinc By similarity
Amino acid modifications
	Modified residue	245	1	Phosphoserine; by CaMK4 and SIK1
	Modified residue	349	1	Phosphoserine By similarity
	Modified residue	465	1	Phosphoserine; by CaMK4 and SIK1 Ref.6 Ref.7
	Modified residue	562	1	Phosphoserine By similarity
	Modified residue	629	1	Phosphoserine; by CaMK4 By similarity
	Modified residue	630	1	Phosphoserine By similarity
	Cross-link	556		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) By similarity
Natural variations
	Alternative sequence	1 – 171	171	Missing in isoform 2.		VSP_023952
	Alternative sequence	732	1	S → SKKLLG in isoform 2.		VSP_023953
Experimental info
	Sequence conflict	569	1	A → S in BAE33147. Ref.1
	Sequence conflict	904	1	R → K in BAE33147. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified July 5, 2004. Version 1. Checksum: A3CCC3CCCBB903A0	FASTA	1,076	118,562
	10 20 30 40 50 60 MSSQSHPDGL SGRDQPVELL NPARVNHMPS TVDVATALPL QVAPTAVPMD LRLDHQFSLP 70 80 90 100 110 120 LEPALREQQL QQELLALKQK QQIQRQILIA EFQRQHEQLS RQHEAQLHEH IKQQQEMLAM 130 140 150 160 170 180 KHQQELLEHQ RKLERHRQEQ ELEKQHREQK LQQLKNKEKG KESAVASTEV KMKLQEFVLN 190 200 210 220 230 240 KKKALAHRNL NHCISSDPRY WYGKTQHSSL DQSSPPQSGV SASYNHPVLG MYDAKDDFPL 250 260 270 280 290 300 RKTASEPNLK LRSRLKQKVA ERRSSPLLRR KDGPVATALK KRPLDVTDSA CSSAPGSGPS 310 320 330 340 350 360 SPNSSSGNVS TENGIAPTVP SAPAETSLAH RLVTREGSVA PLPLYTSPSL PNITLGLPAT 370 380 390 400 410 420 GPAAGAAGQQ DAERLALPAL QQRILFPGTH LTPYLSTSPL ERDGAAAHNP LLQHMVLLEQ 430 440 450 460 470 480 PPTQTPLVTG LGALPLHSQS LVGADRVSPS IHKLRQHRPL GRTQSAPLPQ NAQALQHLVI 490 500 510 520 530 540 QQQHQQFLEK HKQQFQQQQL HLSKIISKPS EPPRQPESHP EETEEELREH QALLDEPYLD 550 560 570 580 590 600 RLPGQKEPSL AGVQVKQEPI ESEEEEAEAT RETEPGQRPA TEQELLFRQQ ALLLEQQRIH 610 620 630 640 650 660 QLRNYQASME AAGIPVSFGS HRPLSRAQSS PASATFPMSV QEPPTKPRFT TGLVYDTLML 670 680 690 700 710 720 KHQCTCGNTN SHPEHAGRIQ SIWSRLQETG LRGKCECIRG RKATLEELQT VHSEAHTLLY 730 740 750 760 770 780 GTNPLNRQKL DSSLTSVFVR LPCGGVGVDS DTIWNEVHSS GAARLAVGCV VELVFKVATG 790 800 810 820 830 840 ELKNGFAVVR PPGHHAEEST PMGFCYFNSV AVAAKLLQQR LNVSKILIVD WDVHHGNGTQ 850 860 870 880 890 900 QAFYNDPNVL YMSLHRYDDG NFFPGSGAPD EVGTGPGVGF NVNMAFTGGL EPPMGDAEYL 910 920 930 940 950 960 AAFRTVVMPI ANEFAPDVVL VSSGFDAVEG HPTPLGGYNL SAKCFGYLTK QLMGLAGGRL 970 980 990 1000 1010 1020 VLALEGGHDL TAICDASEAC VSALLGNELE PLPEKVLHQR PNANAVHSME KVMDIHSKYW 1030 1040 1050 1060 1070 RCLQRLSSTV GHSLIEAQKC EKEEAETVTA MASLSVGVKP AEKRSEEEPM EEEPPL
	Isoform 2 [UniParc]. Checksum: 80C1A8CA5567EE19	FASTA	910	99,124
	10 20 30 40 50 60 MKLQEFVLNK KKALAHRNLN HCISSDPRYW YGKTQHSSLD QSSPPQSGVS ASYNHPVLGM 70 80 90 100 110 120 YDAKDDFPLR KTASEPNLKL RSRLKQKVAE RRSSPLLRRK DGPVATALKK RPLDVTDSAC 130 140 150 160 170 180 SSAPGSGPSS PNSSSGNVST ENGIAPTVPS APAETSLAHR LVTREGSVAP LPLYTSPSLP 190 200 210 220 230 240 NITLGLPATG PAAGAAGQQD AERLALPALQ QRILFPGTHL TPYLSTSPLE RDGAAAHNPL 250 260 270 280 290 300 LQHMVLLEQP PTQTPLVTGL GALPLHSQSL VGADRVSPSI HKLRQHRPLG RTQSAPLPQN 310 320 330 340 350 360 AQALQHLVIQ QQHQQFLEKH KQQFQQQQLH LSKIISKPSE PPRQPESHPE ETEEELREHQ 370 380 390 400 410 420 ALLDEPYLDR LPGQKEPSLA GVQVKQEPIE SEEEEAEATR ETEPGQRPAT EQELLFRQQA 430 440 450 460 470 480 LLLEQQRIHQ LRNYQASMEA AGIPVSFGSH RPLSRAQSSP ASATFPMSVQ EPPTKPRFTT 490 500 510 520 530 540 GLVYDTLMLK HQCTCGNTNS HPEHAGRIQS IWSRLQETGL RGKCECIRGR KATLEELQTV 550 560 570 580 590 600 HSEAHTLLYG TNPLNRQKLD SKKLLGSLTS VFVRLPCGGV GVDSDTIWNE VHSSGAARLA 610 620 630 640 650 660 VGCVVELVFK VATGELKNGF AVVRPPGHHA EESTPMGFCY FNSVAVAAKL LQQRLNVSKI 670 680 690 700 710 720 LIVDWDVHHG NGTQQAFYND PNVLYMSLHR YDDGNFFPGS GAPDEVGTGP GVGFNVNMAF 730 740 750 760 770 780 TGGLEPPMGD AEYLAAFRTV VMPIANEFAP DVVLVSSGFD AVEGHPTPLG GYNLSAKCFG 790 800 810 820 830 840 YLTKQLMGLA GGRLVLALEG GHDLTAICDA SEACVSALLG NELEPLPEKV LHQRPNANAV 850 860 870 880 890 900 HSMEKVMDIH SKYWRCLQRL SSTVGHSLIE AQKCEKEEAE TVTAMASLSV GVKPAEKRSE 910 EEPMEEEPPL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). Strain: C57BL/6J and NOD. Tissue: Dendritic cell, Epididymis and Testis.
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Strain: C57BL/6. Tissue: Brain.
[3]	"Modulation of smooth muscle gene expression by association of histone acetyltransferases and deacetylases with myocardin." Cao D., Wang Z., Zhang C.L., Oh J., Xing W., Li S., Richardson J.A., Wang D.Z., Olson E.N. Mol. Cell. Biol. 25:364-376(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MYOCD.
[4]	"Molecular mechanism of transcriptional repression of AhR repressor involving ANKRA2, HDAC4, and HDAC5." Oshima M., Mimura J., Yamamoto M., Fujii-Kuriyama Y. Biochem. Biophys. Res. Commun. 364:276-282(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH AHRR.
[5]	"CaMKIIdelta isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional responses." Zhang T., Kohlhaas M., Backs J., Mishra S., Phillips W., Dybkova N., Chang S., Ling H., Bers D.M., Maier L.S., Olson E.N., Brown J.H. J. Biol. Chem. 282:35078-35087(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION BY CAMK2D.
[6]	"SIK1 is a class II HDAC kinase that promotes survival of skeletal myocytes." Berdeaux R., Goebel N., Banaszynski L., Takemori H., Wandless T., Shelton G.D., Montminy M. Nat. Med. 13:597-603(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-465 AND SER-465.
[7]	"Large scale localization of protein phosphorylation by use of electron capture dissociation mass spectrometry." Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J. Mol. Cell. Proteomics 8:904-912(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-465, MASS SPECTROMETRY. Tissue: Embryonic fibroblast.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AK029933 mRNA. Translation: BAE43272.1. AK155250 mRNA. Translation: BAE33147.1. AK162369 mRNA. Translation: BAE36877.1. BC066052 mRNA. Translation: AAH66052.1.
IPI	IPI00411004. IPI00466540.
RefSeq	NP_997108.1. NM_207225.1.
UniGene	Mm.318567.
3D structure databases
HSSP	HSSP built from PDB template 1ZZ0 based on UniProtKB Q70I53.
ProteinModelPortal	Q6NZM9.
SMR	Q6NZM9. Positions 62-128, 647-1043.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-36317N.
IntAct	Q6NZM9. 4 interactions.
PTM databases
PhosphoSite	Q6NZM9.
Proteomic databases
PaxDb	Q6NZM9.
PRIDE	Q6NZM9.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000008995; ENSMUSP00000008995; ENSMUSG00000026313.
GeneID	208727.
KEGG	mmu:208727.
UCSC	uc007cbe.1. mouse. uc007cbf.1. mouse.
Organism-specific databases
CTD	9759.
MGI	MGI:3036234. Hdac4.
Phylogenomic databases
eggNOG	COG0123.
GeneTree	ENSGT00530000062809.
HOGENOM	HOG000232065.
HOVERGEN	HBG057100.
InParanoid	Q6NZM9.
KO	K11406.
OMA	VSFGGHR.
OrthoDB	EOG44MXRC.
Gene expression databases
Bgee	Q6NZM9.
CleanEx	MM_HDAC4.
Genevestigator	Q6NZM9.
Family and domain databases
Gene3D	3.40.800.20. 1 hit.
InterPro	IPR000286. His_deacetylse. IPR023801. His_deacetylse_dom. IPR024643. Hist_deacetylase_Gln_rich_N. IPR017320. Histone_deAcase_II_euk. [Graphical view]
PANTHER	PTHR10625. PTHR10625. 1 hit.
Pfam	PF12203. HDAC4_Gln. 1 hit. PF00850. Hist_deacetyl. 1 hit. [Graphical view]
PIRSF	PIRSF037911. HDAC_II_euk. 1 hit.
PRINTS	PR01270. HDASUPER.
ProtoNet	Search...
Other
NextBio	372399.
SOURCE	Search...

Entry information

Entry name

HDAC4_MOUSE

Accession

Primary (citable) accession number: Q6NZM9
Secondary accession number(s): Q3TRZ9, Q3U2J3, Q3V3Y4

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 20, 2007
Last sequence update:	July 5, 2004
Last modified:	April 3, 2013
This is version 80 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program