KDM6A_MOUSE
ID KDM6A_MOUSE Reviewed; 1401 AA.
AC O70546; A2AID2; Q6DI80; Q7TSG4;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 09-JAN-2007, sequence version 2.
DT 03-AUG-2022, entry version 170.
DE RecName: Full=Lysine-specific demethylase 6A;
DE EC=1.14.11.68 {ECO:0000250|UniProtKB:O15550};
DE AltName: Full=Histone demethylase UTX;
DE AltName: Full=Ubiquitously transcribed TPR protein on the X chromosome;
DE AltName: Full=Ubiquitously transcribed X chromosome tetratricopeptide repeat protein;
DE AltName: Full=[histone H3]-trimethyl-L-lysine(27) demethylase 6A {ECO:0000305};
GN Name=Kdm6a; Synonyms=Utx;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 255-1401 (ISOFORM 1).
RC STRAIN=C57BL/6J; TISSUE=Embryonic germ cell, and Limb;
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 [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 69-1401 (ISOFORM 1).
RC STRAIN=C57BL/6J; TISSUE=Embryo;
RX PubMed=9499428; DOI=10.1093/hmg/7.4.737;
RA Greenfield A., Carrel L., Pennisi D., Phillippe C., Quaderi N., Siggers P.,
RA Steiner K., Tam P.P.L., Monaco A.P., Willard H.F., Koopman P.;
RT "The UTX gene escapes X inactivation in mice and humans.";
RL Hum. Mol. Genet. 7:737-742(1998).
RN [4]
RP INTERACTION WITH TLE1.
RX PubMed=9854018; DOI=10.1042/bj3370013;
RA Grbavec D., Lo R., Liu Y., Greenfield A., Stifani S.;
RT "Groucho/transducin-like enhancer of split (TLE) family members interact
RT with the yeast transcriptional co-repressor SSN6 and mammalian SSN6-related
RT proteins: implications for evolutionary conservation of transcription
RT repression mechanisms.";
RL Biochem. J. 337:13-17(1999).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic brain;
RX PubMed=15345747; DOI=10.1074/mcp.m400085-mcp200;
RA Ballif B.A., Villen J., Beausoleil S.A., Schwartz D., Gygi S.P.;
RT "Phosphoproteomic analysis of the developing mouse brain.";
RL Mol. Cell. Proteomics 3:1093-1101(2004).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-769; THR-827 AND SER-829, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Kidney, Lung, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [7]
RP FUNCTION, AND INTERACTION WITH SMARCA4.
RX PubMed=21095589; DOI=10.1016/j.molcel.2010.10.028;
RA Miller S.A., Mohn S.E., Weinmann A.S.;
RT "Jmjd3 and UTX play a demethylase-independent role in chromatin remodeling
RT to regulate T-box family member-dependent gene expression.";
RL Mol. Cell 40:594-605(2010).
RN [8]
RP INTERACTION WITH SUPT6H.
RX PubMed=23503590; DOI=10.1038/emboj.2013.54;
RA Wang A.H., Zare H., Mousavi K., Wang C., Moravec C.E., Sirotkin H.I.,
RA Ge K., Gutierrez-Cruz G., Sartorelli V.;
RT "The histone chaperone Spt6 coordinates histone H3K27 demethylation and
RT myogenesis.";
RL EMBO J. 32:1075-1086(2013).
RN [9]
RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-519 AND ARG-549, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryo;
RX PubMed=24129315; DOI=10.1074/mcp.o113.027870;
RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M.,
RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V.,
RA Bedford M.T., Comb M.J.;
RT "Immunoaffinity enrichment and mass spectrometry analysis of protein
RT methylation.";
RL Mol. Cell. Proteomics 13:372-387(2014).
CC -!- FUNCTION: Histone demethylase that specifically demethylates 'Lys-27'
CC of histone H3, thereby playing a central role in histone code.
CC Demethylates trimethylated and dimethylated but not monomethylated H3
CC 'Lys-27'. Plays a central role in regulation of posterior development,
CC by regulating HOX gene expression. Demethylation of 'Lys-27' of histone
CC H3 is concomitant with methylation of 'Lys-4' of histone H3, and
CC regulates the recruitment of the PRC1 complex and monoubiquitination of
CC histone H2A (By similarity). Plays a demethylase-independent role in
CC chromatin remodeling to regulate T-box family member-dependent gene
CC expression (PubMed:21095589). {ECO:0000250|UniProtKB:O15550,
CC ECO:0000269|PubMed:21095589}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 2-oxoglutarate + N(6),N(6),N(6)-trimethyl-L-lysyl(27)-
CC [histone H3] + 2 O2 = 2 CO2 + 2 formaldehyde + N(6)-methyl-L-
CC lysyl(27)-[histone H3] + 2 succinate; Xref=Rhea:RHEA:60224,
CC Rhea:RHEA-COMP:15535, Rhea:RHEA-COMP:15544, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:16842,
CC ChEBI:CHEBI:30031, ChEBI:CHEBI:61929, ChEBI:CHEBI:61961;
CC EC=1.14.11.68; Evidence={ECO:0000250|UniProtKB:O15550};
CC -!- COFACTOR:
CC Name=L-ascorbate; Xref=ChEBI:CHEBI:38290; Evidence={ECO:0000250};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033; Evidence={ECO:0000250};
CC -!- SUBUNIT: Component of the MLL2/3 complex (also named ASCOM complex), at
CC least composed of KMT2D/MLL2 or KMT2C/MLL3, ASH2L, RBBP5, WDR5, NCOA6,
CC DPY30, KDM6A (or KDM6B), PAXIP1/PTIP, PAGR1 and alpha- and beta-tubulin
CC (By similarity). Interacts with TLE1 (PubMed:9854018). Interacts with
CC SUPT6H (PubMed:23503590). Interacts with SMARCA4 (PubMed:21095589).
CC {ECO:0000250|UniProtKB:O15550, ECO:0000269|PubMed:21095589,
CC ECO:0000269|PubMed:23503590, ECO:0000269|PubMed:9854018}.
CC -!- INTERACTION:
CC O70546; Q61321: Six4; NbExp=2; IntAct=EBI-1573712, EBI-986524;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O70546-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O70546-2; Sequence=VSP_022196;
CC -!- TISSUE SPECIFICITY: Expressed in brain, heart and spleen.
CC -!- DEVELOPMENTAL STAGE: Widely expressed at 13.5 dpc.
CC -!- MISCELLANEOUS: Escapes X chromosome inactivation.
CC -!- SIMILARITY: Belongs to the UTX family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH75703.1; Type=Miscellaneous discrepancy; Evidence={ECO:0000305};
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DR EMBL; AL732451; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL773547; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC053433; AAH53433.1; -; mRNA.
DR EMBL; BC075703; AAH75703.1; ALT_INIT; mRNA.
DR EMBL; AJ002730; CAA05692.1; -; mRNA.
DR CCDS; CCDS30037.1; -. [O70546-2]
DR CCDS; CCDS81102.1; -. [O70546-1]
DR RefSeq; NP_001297373.1; NM_001310444.1. [O70546-1]
DR RefSeq; NP_033509.1; NM_009483.2. [O70546-2]
DR AlphaFoldDB; O70546; -.
DR SMR; O70546; -.
DR BioGRID; 204471; 9.
DR IntAct; O70546; 6.
DR MINT; O70546; -.
DR STRING; 10090.ENSMUSP00000061539; -.
DR iPTMnet; O70546; -.
DR PhosphoSitePlus; O70546; -.
DR EPD; O70546; -.
DR MaxQB; O70546; -.
DR PaxDb; O70546; -.
DR PeptideAtlas; O70546; -.
DR PRIDE; O70546; -.
DR ProteomicsDB; 264991; -. [O70546-1]
DR ProteomicsDB; 264992; -. [O70546-2]
DR Antibodypedia; 639; 209 antibodies from 26 providers.
DR DNASU; 22289; -.
DR Ensembl; ENSMUST00000044484; ENSMUSP00000045862; ENSMUSG00000037369. [O70546-1]
DR Ensembl; ENSMUST00000052368; ENSMUSP00000061539; ENSMUSG00000037369. [O70546-2]
DR GeneID; 22289; -.
DR KEGG; mmu:22289; -.
DR UCSC; uc009ssk.1; mouse. [O70546-1]
DR UCSC; uc009ssm.1; mouse. [O70546-2]
DR CTD; 7403; -.
DR MGI; MGI:1095419; Kdm6a.
DR VEuPathDB; HostDB:ENSMUSG00000037369; -.
DR eggNOG; KOG1124; Eukaryota.
DR eggNOG; KOG1246; Eukaryota.
DR GeneTree; ENSGT00940000155202; -.
DR HOGENOM; CLU_003187_0_0_1; -.
DR InParanoid; O70546; -.
DR OMA; NCISHRS; -.
DR OrthoDB; 268901at2759; -.
DR TreeFam; TF317405; -.
DR BRENDA; 1.14.11.68; 3474.
DR Reactome; R-MMU-3214842; HDMs demethylate histones.
DR BioGRID-ORCS; 22289; 3 hits in 63 CRISPR screens.
DR ChiTaRS; Kdm6a; mouse.
DR PRO; PR:O70546; -.
DR Proteomes; UP000000589; Chromosome X.
DR RNAct; O70546; protein.
DR Bgee; ENSMUSG00000037369; Expressed in animal zygote and 255 other tissues.
DR ExpressionAtlas; O70546; baseline and differential.
DR Genevisible; O70546; MM.
DR GO; GO:0035097; C:histone methyltransferase complex; IDA:MGI.
DR GO; GO:0044666; C:MLL3/4 complex; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0031490; F:chromatin DNA binding; IDA:MGI.
DR GO; GO:0071558; F:histone H3-tri/di-methyl-lysine-27 demethylase activity; IDA:MGI.
DR GO; GO:0042802; F:identical protein binding; IDA:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; IDA:MGI.
DR GO; GO:0006338; P:chromatin remodeling; IMP:UniProtKB.
DR GO; GO:0072359; P:circulatory system development; IMP:MGI.
DR GO; GO:0048568; P:embryonic organ development; IMP:MGI.
DR GO; GO:0007507; P:heart development; IMP:MGI.
DR GO; GO:0003007; P:heart morphogenesis; IMP:MGI.
DR GO; GO:0071557; P:histone H3-K27 demethylation; IMP:MGI.
DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI.
DR GO; GO:0048333; P:mesodermal cell differentiation; IMP:MGI.
DR GO; GO:0035264; P:multicellular organism growth; IMP:MGI.
DR GO; GO:0001843; P:neural tube closure; IMP:MGI.
DR GO; GO:0021915; P:neural tube development; IMP:MGI.
DR GO; GO:0048570; P:notochord morphogenesis; IMP:MGI.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:MGI.
DR GO; GO:0010468; P:regulation of gene expression; IMP:MGI.
DR GO; GO:0003016; P:respiratory system process; IMP:MGI.
DR GO; GO:0032525; P:somite rostral/caudal axis specification; IMP:MGI.
DR Gene3D; 1.25.40.10; -; 2.
DR InterPro; IPR003347; JmjC_dom.
DR InterPro; IPR011990; TPR-like_helical_dom_sf.
DR InterPro; IPR019734; TPR_repeat.
DR Pfam; PF02373; JmjC; 1.
DR Pfam; PF13181; TPR_8; 1.
DR SMART; SM00558; JmjC; 1.
DR SMART; SM00028; TPR; 6.
DR SUPFAM; SSF48452; SSF48452; 1.
DR PROSITE; PS51184; JMJC; 1.
DR PROSITE; PS50005; TPR; 7.
DR PROSITE; PS50293; TPR_REGION; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Chromatin regulator; Dioxygenase; Iron;
KW Metal-binding; Methylation; Nucleus; Oxidoreductase; Phosphoprotein;
KW Reference proteome; Repeat; TPR repeat; Zinc.
FT CHAIN 1..1401
FT /note="Lysine-specific demethylase 6A"
FT /id="PRO_0000106410"
FT REPEAT 95..128
FT /note="TPR 1"
FT REPEAT 132..165
FT /note="TPR 2"
FT REPEAT 169..203
FT /note="TPR 3"
FT REPEAT 207..240
FT /note="TPR 4"
FT REPEAT 245..285
FT /note="TPR 5"
FT REPEAT 286..319
FT /note="TPR 6"
FT REPEAT 321..353
FT /note="TPR 7"
FT REPEAT 355..387
FT /note="TPR 8"
FT DOMAIN 1095..1258
FT /note="JmjC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00538"
FT REGION 1..1095
FT /note="Interaction with SUPT6H"
FT /evidence="ECO:0000269|PubMed:23503590"
FT REGION 439..463
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 596..745
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 795..863
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 914..941
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1043..1080
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 596..646
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 655..745
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 795..862
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 917..937
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1046..1076
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 1146
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250"
FT BINDING 1148
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250"
FT BINDING 1226
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:O14607"
FT BINDING 1331
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 1334
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 1358
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 1361
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT MOD_RES 519
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0007744|PubMed:24129315"
FT MOD_RES 549
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0007744|PubMed:24129315"
FT MOD_RES 769
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 827
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 829
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT VAR_SEQ 1393..1401
FT /note="APPLPSASS -> VSEINMLLHYHPPHLDIVPWTLNMRPFLLFRK (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_022196"
FT CONFLICT 321
FT /note="D -> G (in Ref. 2; AAH75703)"
FT /evidence="ECO:0000305"
FT CONFLICT 1198
FT /note="E -> G (in Ref. 2; AAH75703)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1401 AA; 154355 MW; 293DA417F49EECFF CRC64;
MKSCGVSLAT AAAAAAAAAF GDEEKKMAAG KASGESEEAS PSLTAEEREA LGGLDSRLFG
FVRFHEDGAR MKALLGKAVR CYESLILKAE GKVESDFFCQ LGHFNLLLED YPKALSAYQR
YYSLQSDYWK NAAFLYGLGL VYFHYNAFQW AIKAFQEVLY VDPSFCRAKE IHLRLGLMFK
VNTDYESSLK HFQLALVDCN PCTLSNAEIQ FHIAHLYETQ RKYHSAKEAY EQLLQTENLS
AQVKATILQQ LGWMHHTVDL LGDKATKESY AIQYLQKSLE ADPNSGQSWY FLGRCYSSIG
KVQDAFISYR QSIDKSEASA DTWCSIGVLY QQQNQPMDAL QAYICAVQLD HGHAAAWMDL
GTLYESCNQP QDAIKCYLNA TRSKNCSNTS GLAARIKYLQ AQLCNLPQGS LQNKTKLLPS
IEEAWSLPIP AELTSRQGAM NTAQQNTSDN WSGGNAPPPV EQQTHSWCLT PQKLQHLEQL
RANRNNLNPA QKLMLEQLES QFVLMQQHQM RQTGVAQVRP TGILNGPTVD SSLPTNSVSG
QQPQLPLTRM PSVSQPGVHT ACPRQTLANG PFSAGHVPCS TSRTLGSTDT VLIGNNHVTG
SGSNGNVPYL QRNAPTLPHN RTNLTSSTEE PWKNQLSNST QGLHKGPSSH LAGPNGERPL
SSTGPSQHLQ AAGSGIQNQN GHPTLPSNSV TQGAALNHLS SHTATSGGQQ GITLTKESKP
SGNTLTVPET SRQTGETPNS TASVEGLPNH VHQVMADAVC SPSHGDSKSP GLLSSDNPQL
SALLMGKANN NVGPGTCDKV NNIHPTVHTK TDNSVASSPS SAISTATPSP KSTEQTTTNS
VTSLNSPHSG LHTINGEGME ESQSPIKTDL LLVSHRPSPQ IIPSMSVSIY PSSAEVLKAC
RNLGKNGLSN SSILLDKCPP PRPPSSPYPP LPKDKLNPPT PSIYLENKRD AFFPPLHQFC
TNPNNPVTVI RGLAGALKLD LGLFSTKTLV EANNEHMVEV RTQLLQPADE NWDPTGTKKI
WHCESNRSHT TIAKYAQYQA SSFQESLREE NEKRSHHKDH SDSESTSSDN SGKRRKGPFK
TIKFGTNIDL SDDKKWKLQL HELTKLPAFV RVVSAGNLLS HVGHTILGMN TVQLYMKVPG
SRTPGHQENN NFCSVNINIG PGDCEWFVVP EGYWGVLNDF CEKNNLNFLM GSWWPNLEDL
YEANVPVYRF IQRPGDLVWI NAGTVHWVQA IGWCNNIAWN VGPLTACQYK LAVERYEWNK
LQNVKSIVPM VHLSWNMARN IKVSDPKLFE MIKYCLLRTL KQCQTLREAL IAAGKEIIWH
GRTKEEPAHY CSICEVEVFD LLFVTNESNS RKTYIVHCQD CARKTSGNLE NFVVLEQYKM
EDLMQVYDQF TLAPPLPSAS S
