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E9Q5F9 (SETD2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 32. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Histone-lysine N-methyltransferase SETD2

EC=2.1.1.43
Alternative name(s):
Lysine N-methyltransferase 3A
SET domain-containing protein 2
Gene names
Name:Setd2
Synonyms:Kiaa1732, Kmt3a
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length2537 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Histone methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using dimethylated 'Lys-36' (H3K36me2) as substrate. Represents the main enzyme generating H3K36me3, a specific tag for epigenetic transcriptional activation. Plays a role in chromatin structure modulation during elongation by coordinating recruitment of the FACT complex and by interacting with hyperphosphorylated POLR2A. Acts as a key regulator of DNA mismatch repair in G1 and early S phase by generating H3K36me3, a mark required to recruit MSH6 subunit of the MutS alpha complex: early recruitment of the MutS alpha complex to chromatin to be replicated allows a quick identification of mismatch DNA to initiate the mismatch repair reaction. H3K36me3 also plays an essential role in the maintenance of a heterochromatic state, by recruiting DNA methyltransferase DNMT3A. H3K36me3 is also enhanced in intron-containing genes, suggesting that SETD2 recruitment is enhanced by splicing and that splicing is coupled to recruitment of elongating RNA polymerase. Required during angiogenesis. Ref.4 Ref.6

Catalytic activity

S-adenosyl-L-methionine + L-lysine-[histone] = S-adenosyl-L-homocysteine + N(6)-methyl-L-lysine-[histone]. Ref.4

Enzyme regulation

Specifically inhibited by sinefungin derivatives By similarity.

Subunit structure

Specifically interacts with hyperphosphorylated C-terminal domain (CTD) of RNA polymerase II large subunit (POLR2A): binds to CTD heptad repeats doubly phosphorylated on 'Ser-2' and 'Ser-5' of each heptad. Interacts with HTT and IWS1. Interacts with p53/TP53; leading to regulate p53/TP53 target genes. Component of a complex with HNRNPL By similarity.

Subcellular location

Nucleus. Chromosome Ref.4.

Domain

The low charge region mediates the transcriptional activation activity By similarity.

Post-translational modification

May be automethylated By similarity.

Disruption phenotype

Embryonic lethality at E10.5-E11.5. Embryos show severe vascular defects in embryo, yolk sac and placenta. Capillaries are abnormally dilated in embryos and yolk sacs and cannot be remodeled into large blood vessels or intricate networks. The embryonic vessels fail to invade the labyrinthine layer of placenta, which impair the embryonic-maternal vascular connection. Defects are not caused by the extraembryonic tissues. Impaired H3K36me3, but not H3K36me2 or H3K36me1. Ref.6

Sequence similarities

Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. SET2 subfamily.

Contains 1 AWS domain.

Contains 1 post-SET domain.

Contains 1 SET domain.

Contains 1 WW domain.

Ontologies

Keywords
   Biological processTranscription
Transcription regulation
   Cellular componentChromosome
Nucleus
   Coding sequence diversityAlternative splicing
   DomainCoiled coil
   LigandS-adenosyl-L-methionine
   Molecular functionActivator
Chromatin regulator
Methyltransferase
Transferase
   PTMPhosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processangiogenesis

Inferred from mutant phenotype Ref.6. Source: MGI

cell migration involved in vasculogenesis

Inferred from mutant phenotype Ref.6. Source: MGI

coronary vasculature morphogenesis

Inferred from mutant phenotype Ref.6. Source: MGI

embryonic cranial skeleton morphogenesis

Inferred from mutant phenotype Ref.6. Source: MGI

embryonic organ development

Inferred from mutant phenotype Ref.6. Source: MGI

embryonic placenta morphogenesis

Inferred from mutant phenotype Ref.6. Source: MGI

forebrain development

Inferred from mutant phenotype Ref.6. Source: MGI

histone H3-K36 methylation

Inferred from mutant phenotype Ref.4Ref.6. Source: MGI

histone H3-K36 trimethylation

Inferred from sequence or structural similarity. Source: UniProtKB

mesoderm morphogenesis

Inferred from mutant phenotype Ref.6. Source: MGI

mismatch repair

Inferred from sequence or structural similarity. Source: UniProtKB

morphogenesis of a branching structure

Inferred from mutant phenotype Ref.6. Source: MGI

neural tube closure

Inferred from mutant phenotype Ref.6. Source: MGI

nucleosome organization

Inferred from sequence or structural similarity. Source: UniProtKB

peptidyl-lysine trimethylation

Inferred from mutant phenotype Ref.4Ref.6. Source: MGI

pericardium development

Inferred from mutant phenotype Ref.6. Source: MGI

regulation of gene expression

Inferred from mutant phenotype Ref.6. Source: MGI

regulation of mRNA export from nucleus

Inferred from electronic annotation. Source: Ensembl

regulation of transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

stem cell development

Inferred from mutant phenotype Ref.6. Source: MGI

transcription elongation from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: UniProtKB

vasculogenesis

Inferred from mutant phenotype Ref.6. Source: MGI

   Cellular_componentchromosome

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from direct assay Ref.4. Source: MGI

   Molecular_functionhistone-lysine N-methyltransferase activity

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: E9Q5F9-1)

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: E9Q5F9-2)

The sequence of this isoform differs from the canonical sequence as follows:
     2011-2011: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 25372537Histone-lysine N-methyltransferase SETD2
PRO_0000423553

Regions

Domain1468 – 152255AWS
Domain1524 – 1641118SET
Domain1648 – 166417Post-SET
Domain2362 – 239534WW
Region1534 – 15363Inhibitor binding By similarity
Region1534 – 15363S-adenosyl-L-methionine binding By similarity
Region1577 – 15793Inhibitor binding By similarity
Region1577 – 15793S-adenosyl-L-methionine binding By similarity
Region1602 – 16032Inhibitor binding By similarity
Region1602 – 16032S-adenosyl-L-methionine binding By similarity
Region2110 – 2339230Low charge region By similarity
Region2430 – 2537108Interaction with POLR2A By similarity
Coiled coil2090 – 211930 Potential
Compositional bias167 – 23165Pro-rich
Compositional bias294 – 439146Ser-rich
Compositional bias369 – 45789Arg-rich
Compositional bias2233 – 2338106Gln-rich

Sites

Binding site15991Inhibitor By similarity
Binding site16501Inhibitor; alternate By similarity
Binding site16501S-adenosyl-L-methionine; alternate By similarity
Binding site16531Inhibitor; via amide nitrogen; alternate By similarity
Binding site16531S-adenosyl-L-methionine; via amide nitrogen; alternate By similarity

Amino acid modifications

Modified residue1321Phosphoserine By similarity
Modified residue3221Phosphoserine By similarity
Modified residue3241Phosphoserine By similarity
Modified residue6241Phosphoserine By similarity
Modified residue7071Phosphoserine By similarity
Modified residue7431Phosphoserine By similarity
Modified residue7531Phosphoserine By similarity
Modified residue12011Phosphoserine By similarity
Modified residue13871Phosphoserine Ref.5
Modified residue13891Phosphoserine Ref.5
Modified residue13911Phosphoserine Ref.5
Modified residue18461Phosphothreonine By similarity
Modified residue20531Phosphoserine By similarity
Modified residue20551Phosphoserine By similarity

Natural variations

Alternative sequence20111Missing in isoform 2.
VSP_047946

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified April 5, 2011. Version 1.
Checksum: 4ED47D778291DA9D

FASTA2,537285,663
        10         20         30         40         50         60 
MKPLPSQQPP PKMGDFYDPE HPTPEEEENE AKIENVQKTG FIKGPVFKGV ASSRFLPKGT 

        70         80         90        100        110        120 
KTKVNLEEQG RQKVSFSFSF TKKTLQNRFL TALSNEKQSD SPNSPAPPLQ VDSNPKVKMD 

       130        140        150        160        170        180 
AGDTFPATEE SSPPKSRVEL GRIHFKKHLL HVTSRPQLAA STTAASPLPP TTQLPAVLAE 

       190        200        210        220        230        240 
SMIDSPPSSP PPPPPPPQAS SPSPPAQISE PVALPQPPAT ALMTSPPGPL PGDVAVRAQK 

       250        260        270        280        290        300 
ESPVKSGPEV LEVDTKQDIV SNSLEEHTVQ TLKEQADHLL QKEDSHIGKE EEVSDGSKIS 

       310        320        330        340        350        360 
LSSKKASSKK KSSQFEGTFL GSESDEDSVR TSSSQRSHDL KSSTSIDKER DFKKSSAPSK 

       370        380        390        400        410        420 
SEDLGKSSRS KTERDDRYCS YSKLERDTRY VSSRCRSERD RRRSRSRSRS DRASRTSLSY 

       430        440        450        460        470        480 
SRSERSHYYD SERRYHRSSP YRERTRYSRP YTDNRARESS DSEDEYKKTY PRRTSAHSYR 

       490        500        510        520        530        540 
DLRTSSSYSK FDRDCKTETS YLEMERRGKY TSKLERESKR TSEHETIKRC CSPPNELGFR 

       550        560        570        580        590        600 
RGSSYSKHDN STSRYKSALS KSISKNDKFK NSFCCTELNE ENKQSHSFSL QTPCSKGSEL 

       610        620        630        640        650        660 
RTINKISERE KTGSPTPSNQ LNDSPTFKKL DESPVLKPEF IGHDGRESIK ELELSKVKND 

       670        680        690        700        710        720 
QLRNFCSIEL NVNGSPETEA DVATFCTSKT DAISMTSDDS VTGSEVSPLI KACMLSSNGF 

       730        740        750        760        770        780 
QNVGRCRERD SDDTCRQHNT SKSPFREMEP LLSPHHDKLM SLPVKTIDYP KTLIKEPVDK 

       790        800        810        820        830        840 
RHSCCKTKDS DIYCSPNENP EAENAEPSAM TISSHSFVNV HLESKTVICD NREPTDRHSE 

       850        860        870        880        890        900 
NTCDEYKQSI GSTSSASHNH FDGLYEPIGS SGISSLQSPP SGIRCEENTS PTLDAVESKK 

       910        920        930        940        950        960 
GIDFLKYARK ETDVGSALPD SGKGFSWENR HNNVLSGQSL QEAQEEGNSI LHERRGRPEI 

       970        980        990       1000       1010       1020 
PLDEEQRGHT HISDDSEVVF PYDLNLTMED SDGITYTLKC DSSGNAPEIV STVHEDYSGS 

      1030       1040       1050       1060       1070       1080 
SASSSDESDS EDTESDDSSI PRNRLQSVVV VPKNSTLPME ETSPCSSRSS QSYKHYSDRW 

      1090       1100       1110       1120       1130       1140 
EDGLETRRHA YEEEYESKGC SQTEKYFLHK GTERSAESCY SQFGRKADNH LPDIAHAQSD 

      1150       1160       1170       1180       1190       1200 
GVDSTSQTDS RSDHLGHLNP EDTLRAKTSR PQELPVYSDD FEDLPNKSRQ QMIFSNRPDS 

      1210       1220       1230       1240       1250       1260 
SRLGKTELSF SSSCDISRMD GLHSSEELRN LGWDFSQQER PTTTYQQPDS SYGTCGTHKY 

      1270       1280       1290       1300       1310       1320 
QQSTEHYGGT HNYWQGNGYW DPRSAGRPPG TGLAYDRIQG QVPDSLTDDR EEEEHWDQRS 

      1330       1340       1350       1360       1370       1380 
GSHFSSPSNK FFFHQKDKGS VQAPEISSNS IKDALVMNER KDFSKNFEKN DIKERGPPKK 

      1390       1400       1410       1420       1430       1440 
RRQELESDSE SDGELQARKK VRVEMEQGES SVPQHSELMG PSCAMDDFRD PQRWKEFAKL 

      1450       1460       1470       1480       1490       1500 
GKMPCYFDLI EENVYLTERK KNKSHRDIKR MQCECTPLSK DERAQGEVAC GEDCLNRLLM 

      1510       1520       1530       1540       1550       1560 
IECSSRCPNG DYCSNRRFQR KQHADVEVIL TEKKGWGLRA AKDLPSNTFV LEYCGEVLDH 

      1570       1580       1590       1600       1610       1620 
KEFKARVKEY ARNKNIHYYF MALKNDEIID ATQKGNCSRF MNHSCEPNCE TQKWTVNGQL 

      1630       1640       1650       1660       1670       1680 
RVGFFTTKLV PSGSELTFDY QFQRYGKEAQ KCFCGSANCR GYLGGENRVS IRAAGGKMKK 

      1690       1700       1710       1720       1730       1740 
ERSRKKDSVD GELEALMENG EGLSDKNQVL SLSRLMVRIE TLEQKLTCLK LIQNTHSQSC 

      1750       1760       1770       1780       1790       1800 
LKSFLERHGL SLLWIWMAEL GDGRESNQKL QEEIIKTLEH LPIPTKNMLE ESKVLPIIQR 

      1810       1820       1830       1840       1850       1860 
WSQTKTAVPQ LSEGDGYSSE NTSRAHTPLN TPDPSAKPST EMDTDTPKKL IFRRLKIISE 

      1870       1880       1890       1900       1910       1920 
NSMDSAVSDV TSELECKDGK EDLDQLETVT VEEDEELQSQ QLLPQQLCES KVESEATIEV 

      1930       1940       1950       1960       1970       1980 
SKLPTSEPEA DTETEPKDSN GTKLEETIAE ETPSQDEEEG VSDVESERSQ EPPDKTVDIS 

      1990       2000       2010       2020       2030       2040 
DLATKLLDSW KDLKEVYRIP KKSQTEKEST VAERGRDAAA FRDQTAPKTP NRSRERDPDK 

      2050       2060       2070       2080       2090       2100 
QSQNKEKRKR RGSLSPPSSA YERGTKRPDD RYDTPTSKKK VRIKDRNKLS TEERRKLFEQ 

      2110       2120       2130       2140       2150       2160 
EVAQREAQKQ QQQMQNLGMT SPLPFDSLGY NASHHPFAGY PPGYPMQAYV DPSNPNAGKV 

      2170       2180       2190       2200       2210       2220 
LLPTPSMDPV CSPAPYDHAQ PLVGHSTESL AAPPSVPVVP HVAASVEVSS SQYVAQNESV 

      2230       2240       2250       2260       2270       2280 
VHQDSNVPVM PVQAPGPVQG QNYNVWESNQ QSVSVQQQYS PAQSQTTIYY QGQTCSTVYS 

      2290       2300       2310       2320       2330       2340 
VTSPYSQTTP PIVQSYAQPS LQYIQGQQIF TAHPQGVVVQ PTAAVTSIVA PGQPQSLQPP 

      2350       2360       2370       2380       2390       2400 
EMVVTNNLLD LPPPSPPKPK TIVLPPNWKT ARDPEGKIYY YHVITRQTQW DPPTWESPGD 

      2410       2420       2430       2440       2450       2460 
DASLEHEAEM DLGTPTYDEN PMKTSKKPKT AEADTSSELA KKSKEVFRKE MSQFIVQCLN 

      2470       2480       2490       2500       2510       2520 
PYRKPDCKVG RITTTEDFKH LARKLTHGVM NKELKYCKNP EDLECNENVK HKTKEYIKKY 

      2530 
MQKFGAVYKP KEDTELE 

« Hide

Isoform 2 [UniParc].

Checksum: 990ECF2CD8D56008
Show »

FASTA2,536285,564

References

« Hide 'large scale' references
[1]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: C57BL/6J.
[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] OF 2121-2537 AND 1800-2537 (ISOFORM 2).
Tissue: Mammary tumor.
[3]"Prediction of the coding sequences of mouse homologues of KIAA gene: IV. The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs identified by screening of terminal sequences of cDNA clones randomly sampled from size-fractionated libraries."
Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S., Saga Y., Seino S., Nishimura M., Kaisho T., Hoshino K., Kitamura H., Nagase T., Ohara O., Koga H.
DNA Res. 11:205-218(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1834-2537 (ISOFORM 1).
Tissue: Thymus.
[4]"Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation."
Edmunds J.W., Mahadevan L.C., Clayton A.L.
EMBO J. 27:406-420(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY.
[5]"The phagosomal proteome in interferon-gamma-activated macrophages."
Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P.
Immunity 30:143-154(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1387; SER-1389 AND SER-1391, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[6]"Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling."
Hu M., Sun X.J., Zhang Y.L., Kuang Y., Hu C.Q., Wu W.L., Shen S.H., Du T.T., Li H., He F., Xiao H.S., Wang Z.G., Liu T.X., Lu H., Huang Q.H., Chen S.J., Chen Z.
Proc. Natl. Acad. Sci. U.S.A. 107:2956-2961(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AC132103 Genomic DNA. No translation available.
BC031601 mRNA. Translation: AAH31601.1.
BC059049 mRNA. Translation: AAH59049.1.
AK173246 mRNA. Translation: BAD32524.1.
CCDSCCDS40781.2. [E9Q5F9-1]
RefSeqNP_001074809.2. NM_001081340.2. [E9Q5F9-1]
UniGeneMm.288949.

3D structure databases

ProteinModelPortalE9Q5F9.
SMRE9Q5F9. Positions 1421-1665, 2435-2534.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

STRING10090.ENSMUSP00000116313.

Proteomic databases

PRIDEE9Q5F9.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000153838; ENSMUSP00000116313; ENSMUSG00000044791. [E9Q5F9-1]
GeneID235626.
KEGGmmu:235626.
UCSCuc009rug.2. mouse. [E9Q5F9-1]

Organism-specific databases

CTD29072.
MGIMGI:1918177. Setd2.
RougeSearch...

Phylogenomic databases

GeneTreeENSGT00750000117355.
KOK11423.
OMAVMDDFRD.
OrthoDBEOG7DFXBB.
TreeFamTF106477.

Gene expression databases

ArrayExpressE9Q5F9.
BgeeE9Q5F9.

Family and domain databases

InterProIPR006560. AWS.
IPR003616. Post-SET_dom.
IPR001214. SET_dom.
IPR013257. SRI.
IPR001202. WW_dom.
[Graphical view]
PfamPF00856. SET. 1 hit.
PF08236. SRI. 1 hit.
PF00397. WW. 1 hit.
[Graphical view]
SMARTSM00570. AWS. 1 hit.
SM00508. PostSET. 1 hit.
SM00317. SET. 1 hit.
SM00456. WW. 1 hit.
[Graphical view]
SUPFAMSSF51045. SSF51045. 1 hit.
PROSITEPS51215. AWS. 1 hit.
PS50868. POST_SET. 1 hit.
PS50280. SET. 1 hit.
PS01159. WW_DOMAIN_1. 1 hit.
PS50020. WW_DOMAIN_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio382803.
PROE9Q5F9.
SOURCESearch...

Entry information

Entry nameSETD2_MOUSE
AccessionPrimary (citable) accession number: E9Q5F9
Secondary accession number(s): Q69ZC0, Q6PCY9, Q8K0F3
Entry history
Integrated into UniProtKB/Swiss-Prot: September 18, 2013
Last sequence update: April 5, 2011
Last modified: July 9, 2014
This is version 32 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot