EZH2_MACFA
ID EZH2_MACFA Reviewed; 746 AA.
AC Q4R381; Q4R780;
DT 22-JUL-2008, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 92.
DE RecName: Full=Histone-lysine N-methyltransferase EZH2;
DE EC=2.1.1.356 {ECO:0000250|UniProtKB:Q15910};
DE AltName: Full=Enhancer of zeste homolog 2;
GN Name=EZH2; ORFNames=QtsA-15957, QtsA-18821;
OS Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9541;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Testis;
RG International consortium for macaque cDNA sequencing and analysis;
RT "DNA sequences of macaque genes expressed in brain or testis and its
RT evolutionary implications.";
RL Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Polycomb group (PcG) protein. Catalytic subunit of the
CC PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27'
CC (H3K27me) of histone H3, leading to transcriptional repression of the
CC affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of
CC histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively.
CC Displays a preference for substrates with less methylation, loses
CC activity when progressively more methyl groups are incorporated into
CC H3K27, H3K27me0 > H3K27me1 > H3K27me2. Compared to EZH1-containing
CC complexes, it is more abundant in embryonic stem cells and plays a
CC major role in forming H3K27me3, which is required for embryonic stem
CC cell identity and proper differentiation. The PRC2/EED-EZH2 complex may
CC also serve as a recruiting platform for DNA methyltransferases, thereby
CC linking two epigenetic repression systems. EZH2 can also methylate non-
CC histone proteins such as the transcription factor GATA4 and the nuclear
CC receptor RORA. Regulates the circadian clock via histone methylation at
CC the promoter of the circadian genes. Essential for the CRY1/2-mediated
CC repression of the CLOCK-ARNTL/BMAL1 transcriptional activation of
CC PER1/2. Involved in the di and trimethylation of 'Lys-27' of histone H3
CC on PER1/2 promoters which is necessary for the CRY1/2 proteins to
CC inhibit transcription. {ECO:0000250|UniProtKB:Q15910,
CC ECO:0000250|UniProtKB:Q61188}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-lysyl(27)-[histone H3] + 3 S-adenosyl-L-methionine = 3 H(+)
CC + N(6),N(6),N(6)-trimethyl-L-lysyl(27)-[histone H3] + 3 S-adenosyl-L-
CC homocysteine; Xref=Rhea:RHEA:60292, Rhea:RHEA-COMP:15535, Rhea:RHEA-
CC COMP:15548, ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, ChEBI:CHEBI:57856,
CC ChEBI:CHEBI:59789, ChEBI:CHEBI:61961; EC=2.1.1.356;
CC Evidence={ECO:0000250|UniProtKB:Q15910};
CC -!- SUBUNIT: Component of the PRC2/EED-EZH2 complex, which includes EED,
CC EZH2, SUZ12, RBBP4 and RBBP7 and possibly AEBP2 (By similarity). The
CC minimum components required for methyltransferase activity of the
CC PRC2/EED-EZH2 complex are EED, EZH2 and SUZ12 (By similarity). The PRC2
CC complex may also interact with DNMT1, DNMT3A, DNMT3B and PHF1 via the
CC EZH2 subunit and with SIRT1 via the SUZ12 subunit (By similarity).
CC Interacts with HDAC1 and HDAC2 (By similarity). Binds ATRX via the SET
CC domain (Probable). Interacts with PRAME (By similarity). Interacts with
CC CDYL. Interacts with ARNTL/BMAL1, CLOCK and CRY1 (By similarity).
CC Interacts with DNMT3L; the interaction is direct (By similarity).
CC Interacts with EZHIP; the interaction blocks EZH2 methyltransferase
CC activity (By similarity). Interacts with ZNF263; recruited to the SIX3
CC promoter along with other proteins involved in chromatin modification
CC and transcriptional corepression where it contributes to
CC transcriptional repression (By similarity). Interacts with ARMC12 (By
CC similarity). {ECO:0000250|UniProtKB:Q15910,
CC ECO:0000250|UniProtKB:Q61188}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q15910}.
CC Note=Localizes to the inactive X chromosome in trophoblast stem cells.
CC {ECO:0000250|UniProtKB:Q61188}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q4R381-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q4R381-2; Sequence=VSP_034951, VSP_034952;
CC -!- PTM: Phosphorylated by AKT1. Phosphorylation by AKT1 reduces
CC methyltransferase activity. Phosphorylation at Thr-345 by CDK1 and CDK2
CC promotes maintenance of H3K27me3 levels at EZH2-target loci, thus
CC leading to epigenetic gene silencing. {ECO:0000250|UniProtKB:Q15910}.
CC -!- PTM: Sumoylated. {ECO:0000250|UniProtKB:Q15910}.
CC -!- PTM: Glycosylated: O-GlcNAcylation at Ser-75 by OGT increases stability
CC of EZH2 and facilitates the formation of H3K27me3 by the PRC2/EED-EZH2
CC complex. {ECO:0000250|UniProtKB:Q15910}.
CC -!- SIMILARITY: Belongs to the class V-like SAM-binding methyltransferase
CC superfamily. Histone-lysine methyltransferase family. EZ subfamily.
CC {ECO:0000255|PROSITE-ProRule:PRU00190}.
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DR EMBL; AB168941; BAE01042.1; -; mRNA.
DR EMBL; AB179385; BAE02436.1; -; mRNA.
DR RefSeq; XP_005551149.1; XM_005551092.2.
DR AlphaFoldDB; Q4R381; -.
DR SMR; Q4R381; -.
DR STRING; 9541.XP_005551143.1; -.
DR GeneID; 102146280; -.
DR CTD; 2146; -.
DR eggNOG; KOG1079; Eukaryota.
DR Proteomes; UP000233100; Unplaced.
DR GO; GO:0035098; C:ESC/E(Z) complex; ISS:UniProtKB.
DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
DR GO; GO:0046976; F:histone methyltransferase activity (H3-K27 specific); IEA:UniProtKB-EC.
DR GO; GO:0018024; F:histone-lysine N-methyltransferase activity; ISS:UniProtKB.
DR GO; GO:1990841; F:promoter-specific chromatin binding; ISS:UniProtKB.
DR GO; GO:0006338; P:chromatin remodeling; IEA:InterPro.
DR GO; GO:0070734; P:histone H3-K27 methylation; ISS:UniProtKB.
DR GO; GO:0098532; P:histone H3-K27 trimethylation; ISS:UniProtKB.
DR GO; GO:0045814; P:negative regulation of gene expression, epigenetic; ISS:UniProtKB.
DR GO; GO:0048387; P:negative regulation of retinoic acid receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISS:UniProtKB.
DR GO; GO:0043547; P:positive regulation of GTPase activity; ISS:UniProtKB.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; ISS:UniProtKB.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR CDD; cd00167; SANT; 1.
DR CDD; cd19218; SET_EZH2; 1.
DR Gene3D; 2.170.270.10; -; 1.
DR InterPro; IPR026489; CXC_dom.
DR InterPro; IPR045318; EZH1/2-like.
DR InterPro; IPR021654; EZH1/EZH2.
DR InterPro; IPR044439; EZH2_SET.
DR InterPro; IPR041343; PRC2_HTH_1.
DR InterPro; IPR041355; Pre-SET_CXC.
DR InterPro; IPR001005; SANT/Myb.
DR InterPro; IPR001214; SET_dom.
DR InterPro; IPR046341; SET_dom_sf.
DR InterPro; IPR033467; Tesmin/TSO1-like_CXC.
DR PANTHER; PTHR45747; PTHR45747; 1.
DR Pfam; PF11616; EZH2_WD-Binding; 1.
DR Pfam; PF18118; PRC2_HTH_1; 1.
DR Pfam; PF18264; preSET_CXC; 1.
DR Pfam; PF00856; SET; 1.
DR SMART; SM01114; CXC; 1.
DR SMART; SM00717; SANT; 2.
DR SMART; SM00317; SET; 1.
DR SUPFAM; SSF82199; SSF82199; 1.
DR PROSITE; PS51633; CXC; 1.
DR PROSITE; PS50280; SET; 1.
PE 2: Evidence at transcript level;
KW Alternative splicing; Biological rhythms; Chromatin regulator;
KW Glycoprotein; Isopeptide bond; Methyltransferase; Nucleus; Phosphoprotein;
KW Reference proteome; Repressor; S-adenosyl-L-methionine; Transcription;
KW Transcription regulation; Transferase; Ubl conjugation.
FT CHAIN 1..746
FT /note="Histone-lysine N-methyltransferase EZH2"
FT /id="PRO_0000345426"
FT DOMAIN 503..605
FT /note="CXC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00970"
FT DOMAIN 612..727
FT /note="SET"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00190"
FT REGION 1..340
FT /note="Interaction with DNMT1, DNMT3A and DNMT3B"
FT /evidence="ECO:0000250"
FT REGION 39..68
FT /note="Interaction with EED"
FT /evidence="ECO:0000250"
FT REGION 180..222
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 329..522
FT /note="Interaction with CDYL"
FT /evidence="ECO:0000250"
FT REGION 340..426
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 180..195
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 196..220
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 359..374
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 375..407
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 21
FT /note="Phosphoserine; by PKB/AKT1"
FT /evidence="ECO:0000250|UniProtKB:Q15910"
FT MOD_RES 76
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15910"
FT MOD_RES 339
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q15910"
FT MOD_RES 345
FT /note="Phosphothreonine; by CDK1 and CDK2"
FT /evidence="ECO:0000250|UniProtKB:Q15910"
FT MOD_RES 363
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15910"
FT MOD_RES 366
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15910"
FT MOD_RES 367
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q15910"
FT MOD_RES 487
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q15910"
FT CARBOHYD 75
FT /note="O-linked (GlcNAc) serine"
FT /evidence="ECO:0000250"
FT CROSSLNK 634
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q15910"
FT VAR_SEQ 74..82
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_034951"
FT VAR_SEQ 511..553
FT /note="DGSSNHVYNYQPCDHPRQPCDSSCPCVIAQNFCEKFCQCSSEC -> G (in
FT isoform 2)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_034952"
FT CONFLICT 305
FT /note="A -> T (in Ref. 1; BAE01042)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 746 AA; 85333 MW; 16942199E6E75621 CRC64;
MGQTGKKSEK GPVCWRKRVK SEYMRLRQLK RFRRADEVKS MFSSNRQKIL ERTEILNQEW
KQRRIQPVHI LTSVSSLRGT RECSVTSDLD FPTQVIPLKT LNAVASVPIM YSWSPLQQNF
MVEDETVLHN IPYMGDEVLD QDGTFIEELI KNYDGKVHGD RECGFINDEI FVELVNALGQ
YNDDDDDDDG DDPEEREEKQ KDLEDHRDDK ESRPPRKFPS DKIFEAISSM FPDKGTAEEL
KEKYKELTEQ QLPGALPPEC TPNIDGPNAK SVQREQSLHS FHTLFCRRCF KYDCFLHPFH
ATPNAYKRKN TETALDNKPC GPQCYQHLEG AKEFAAALTA ERIKTPPKRP GGRRRGRLPN
NSSRPSTPTI NVLESKDTDS DREAGTETGG ENNDKEEEEK KDETSSSSEA NSRCQTPIKM
KPNIEPPENV EWSGAEASMF RVLIGTYYDN FCAIARLIGT KTCRQVYEFR VKESSIIAPA
PAEDVDTPPR KKKRKHRLWA AHCRKIQLKK DGSSNHVYNY QPCDHPRQPC DSSCPCVIAQ
NFCEKFCQCS SECQNRFPGC RCKAQCNTKQ CPCYLAVREC DPDLCLTCGA ADHWDSKNVS
CKNCSIQRGS KKHLLLAPSD VAGWGIFIKD PVQKNEFISE YCGEIISQDE ADRRGKVYDK
YMCSFLFNLN NDFVVDATRK GNKIRFANHS VNPNCYAKVM MVNGDHRIGI FAKRAIQTGE
ELFFDYRYSQ ADALKYVGIE REMEIP
