SETD3_MOUSE
ID SETD3_MOUSE Reviewed; 594 AA.
AC Q91WC0; Q6PEN3; Q8CD86; Q8CDX8; Q9CZZ1;
DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=Actin-histidine N-methyltransferase {ECO:0000305};
DE EC=2.1.1.85 {ECO:0000269|PubMed:30626964};
DE AltName: Full=Endothelial differentiation inhibitory protein D10 {ECO:0000303|PubMed:16008511};
DE AltName: Full=Protein-L-histidine N-tele-methyltransferase {ECO:0000305};
DE AltName: Full=SET domain-containing protein 3 {ECO:0000305};
GN Name=Setd3 {ECO:0000312|MGI:MGI:1289184};
GN Synonyms=D12Ertd771e {ECO:0000312|MGI:MGI:1289184};
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 [MRNA] (ISOFORM 1).
RC TISSUE=Embryonic stem cell;
RX PubMed=16008511; DOI=10.1089/dna.2005.24.432;
RA Ishii H., Mimori K., Mori M., Vecchione A.;
RT "Differentially expressed genes in endothelial differentiation.";
RL DNA Cell Biol. 24:432-437(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 3 AND 4).
RC STRAIN=C57BL/6J; TISSUE=Head, Stomach, Testis, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC STRAIN=FVB/N, and NMRI; TISSUE=Eye, Liver, and Mammary tumor;
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 [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Heart, Kidney, Liver, Lung, Pancreas, Spleen, and Testis;
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 [5]
RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND INTERACTION WITH MYOD1.
RX PubMed=21832073; DOI=10.1074/jbc.m110.203307;
RA Eom G.H., Kim K.B., Kim J.H., Kim J.Y., Kim J.R., Kee H.J., Kim D.W.,
RA Choe N., Park H.J., Son H.J., Choi S.Y., Kook H., Seo S.B.;
RT "Histone methyltransferase SETD3 regulates muscle differentiation.";
RL J. Biol. Chem. 286:34733-34742(2011).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND DISRUPTION PHENOTYPE.
RX PubMed=30626964; DOI=10.1038/s41586-018-0821-8;
RA Wilkinson A.W., Diep J., Dai S., Liu S., Ooi Y.S., Song D., Li T.M.,
RA Horton J.R., Zhang X., Liu C., Trivedi D.V., Ruppel K.M.,
RA Vilches-Moure J.G., Casey K.M., Mak J., Cowan T., Elias J.E.,
RA Nagamine C.M., Spudich J.A., Cheng X., Carette J.E., Gozani O.;
RT "SETD3 is an actin histidine methyltransferase that prevents primary
RT dystocia.";
RL Nature 565:372-376(2019).
RN [7]
RP INDUCTION.
RX PubMed=30796205; DOI=10.1038/s41419-019-1432-5;
RA Zhao M.J., Xie J., Shu W.J., Wang H.Y., Bi J., Jiang W., Du H.N.;
RT "MiR-15b and miR-322 inhibit SETD3 expression to repress muscle cell
RT differentiation.";
RL Cell Death Dis. 10:183-183(2019).
CC -!- FUNCTION: Protein-histidine N-methyltransferase that specifically
CC mediates 3-methylhistidine (tele-methylhistidine) methylation of actin
CC at 'His-73' (PubMed:30626964). Histidine methylation of actin is
CC required for smooth muscle contraction of the laboring uterus during
CC delivery (PubMed:30626964). Does not have protein-lysine N-
CC methyltransferase activity and probably only catalyzes histidine
CC methylation of actin (PubMed:30626964). {ECO:0000269|PubMed:30626964}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-histidyl-[protein] + S-adenosyl-L-methionine = H(+) +
CC N(tele)-methyl-L-histidyl-[protein] + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:19369, Rhea:RHEA-COMP:9745, Rhea:RHEA-COMP:11600,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16367, ChEBI:CHEBI:29979,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:59789; EC=2.1.1.85;
CC Evidence={ECO:0000269|PubMed:30626964};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19370;
CC Evidence={ECO:0000269|PubMed:30626964};
CC -!- SUBUNIT: Interacts with MYOD1. {ECO:0000269|PubMed:21832073}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q86TU7}. Nucleus
CC {ECO:0000269|PubMed:21832073}. Note=Localizes mainly in the cytoplasm.
CC {ECO:0000250|UniProtKB:Q86TU7}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q91WC0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q91WC0-2; Sequence=VSP_021195, VSP_021196;
CC Name=3;
CC IsoId=Q91WC0-3; Sequence=VSP_021194;
CC Name=4;
CC IsoId=Q91WC0-4; Sequence=VSP_021195, VSP_021197, VSP_021198;
CC -!- TISSUE SPECIFICITY: Prominently expressed in the heart and skeletal
CC muscles and is also detected weakly in the stomach, small intestine,
CC and colon. {ECO:0000269|PubMed:21832073}.
CC -!- INDUCTION: Expression is repressed by microRNAs miR-15b and miR-322,
CC repressing muscle cell differentiation. {ECO:0000269|PubMed:30796205}.
CC -!- DOMAIN: The SET domain specifically recognizes and binds actin,
CC suggesting that it does not accommodate substrates diverging from
CC actin. {ECO:0000250|UniProtKB:Q86TU7}.
CC -!- PTM: Phosphorylated by GSK3B, which is required for recognition by the
CC SCF(FBXW7) complex and subsequent degradation.
CC {ECO:0000250|UniProtKB:Q86TU7}.
CC -!- PTM: Ubiquitinated by the SCF(FBXW7) complex following phosphorylation
CC by GSK3B, leading to its degradation by the proteasome.
CC {ECO:0000250|UniProtKB:Q86TU7}.
CC -!- DISRUPTION PHENOTYPE: Mice are viable, but females display severely
CC decreased litter sizes due to primary maternal dystocia (delayed
CC parturition) that is refractory to ecbolic induction agents
CC (PubMed:30626964). Cells show complete loss of actin histidine
CC methylation (PubMed:30626964). {ECO:0000269|PubMed:30626964}.
CC -!- SIMILARITY: Belongs to the class V-like SAM-binding methyltransferase
CC superfamily. SETD3 actin-histidine methyltransferase family.
CC {ECO:0000255|PROSITE-ProRule:PRU00898}.
CC -!- CAUTION: Was initially reported to have histone methyltransferase
CC activity and methylate 'Lys-4' and 'Lys-36' of histone H3 (H3K4me and
CC H3K36me) (PubMed:21832073). However, this conclusion was based on mass
CC spectrometry data wherin mass shifts were inconsistent with a bona fide
CC methylation event and the histone methyltransferase activity could not
CC be confirmed (PubMed:30626964). {ECO:0000269|PubMed:21832073,
CC ECO:0000269|PubMed:30626964}.
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DR EMBL; AY513271; AAS82953.1; -; mRNA.
DR EMBL; AK011993; BAB27964.1; -; mRNA.
DR EMBL; AK029403; BAC26435.1; -; mRNA.
DR EMBL; AK031017; BAC27215.1; -; mRNA.
DR EMBL; AK031371; BAC27371.1; -; mRNA.
DR EMBL; AK146777; BAE27425.1; -; mRNA.
DR EMBL; AK166570; BAE38861.1; -; mRNA.
DR EMBL; BC016123; AAH16123.1; -; mRNA.
DR EMBL; BC019973; AAH19973.1; -; mRNA.
DR EMBL; BC057968; AAH57968.1; -; mRNA.
DR CCDS; CCDS26159.1; -. [Q91WC0-1]
DR RefSeq; NP_082538.2; NM_028262.3. [Q91WC0-1]
DR RefSeq; XP_006516144.3; XM_006516081.3. [Q91WC0-2]
DR RefSeq; XP_006516146.1; XM_006516083.3.
DR AlphaFoldDB; Q91WC0; -.
DR SMR; Q91WC0; -.
DR BioGRID; 206736; 8.
DR IntAct; Q91WC0; 6.
DR STRING; 10090.ENSMUSP00000066413; -.
DR iPTMnet; Q91WC0; -.
DR PhosphoSitePlus; Q91WC0; -.
DR EPD; Q91WC0; -.
DR jPOST; Q91WC0; -.
DR MaxQB; Q91WC0; -.
DR PaxDb; Q91WC0; -.
DR PeptideAtlas; Q91WC0; -.
DR PRIDE; Q91WC0; -.
DR ProteomicsDB; 257123; -. [Q91WC0-1]
DR ProteomicsDB; 257124; -. [Q91WC0-2]
DR ProteomicsDB; 257125; -. [Q91WC0-3]
DR ProteomicsDB; 257126; -. [Q91WC0-4]
DR Antibodypedia; 147; 173 antibodies from 24 providers.
DR DNASU; 52690; -.
DR Ensembl; ENSMUST00000071095; ENSMUSP00000066413; ENSMUSG00000056770. [Q91WC0-1]
DR GeneID; 52690; -.
DR KEGG; mmu:52690; -.
DR UCSC; uc007ozj.2; mouse. [Q91WC0-1]
DR UCSC; uc007ozk.2; mouse. [Q91WC0-2]
DR UCSC; uc007ozl.2; mouse. [Q91WC0-4]
DR CTD; 84193; -.
DR MGI; MGI:1289184; Setd3.
DR VEuPathDB; HostDB:ENSMUSG00000056770; -.
DR eggNOG; KOG1337; Eukaryota.
DR GeneTree; ENSGT00940000153577; -.
DR HOGENOM; CLU_028272_0_0_1; -.
DR InParanoid; Q91WC0; -.
DR OMA; DFWMKIP; -.
DR OrthoDB; 489371at2759; -.
DR PhylomeDB; Q91WC0; -.
DR TreeFam; TF354226; -.
DR Reactome; R-MMU-3214841; PKMTs methylate histone lysines.
DR BioGRID-ORCS; 52690; 3 hits in 76 CRISPR screens.
DR ChiTaRS; Setd3; mouse.
DR PRO; PR:Q91WC0; -.
DR Proteomes; UP000000589; Chromosome 12.
DR RNAct; Q91WC0; protein.
DR Bgee; ENSMUSG00000056770; Expressed in hindlimb stylopod muscle and 60 other tissues.
DR ExpressionAtlas; Q91WC0; baseline and differential.
DR Genevisible; Q91WC0; MM.
DR GO; GO:0000785; C:chromatin; IDA:MGI.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0003779; F:actin binding; IEA:UniProtKB-KW.
DR GO; GO:0046975; F:histone methyltransferase activity (H3-K36 specific); IDA:MGI.
DR GO; GO:0042800; F:histone methyltransferase activity (H3-K4 specific); IDA:MGI.
DR GO; GO:0018064; F:protein-L-histidine N-tele-methyltransferase activity; IMP:UniProtKB.
DR GO; GO:0016279; F:protein-lysine N-methyltransferase activity; IBA:GO_Central.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:MGI.
DR GO; GO:0003713; F:transcription coactivator activity; ISS:UniProtKB.
DR GO; GO:0030047; P:actin modification; IMP:UniProtKB.
DR GO; GO:0010452; P:histone H3-K36 methylation; ISS:UniProtKB.
DR GO; GO:0018021; P:peptidyl-histidine methylation; IMP:UniProtKB.
DR GO; GO:0018027; P:peptidyl-lysine dimethylation; ISS:UniProtKB.
DR GO; GO:0018026; P:peptidyl-lysine monomethylation; ISS:UniProtKB.
DR GO; GO:0018023; P:peptidyl-lysine trimethylation; ISS:UniProtKB.
DR GO; GO:0051149; P:positive regulation of muscle cell differentiation; IMP:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:MGI.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0070472; P:regulation of uterine smooth muscle contraction; IMP:UniProtKB.
DR CDD; cd19176; SET_SETD3; 1.
DR Gene3D; 3.90.1420.10; -; 1.
DR InterPro; IPR015353; Rubisco_LSMT_subst-bd.
DR InterPro; IPR036464; Rubisco_LSMT_subst-bd_sf.
DR InterPro; IPR001214; SET_dom.
DR InterPro; IPR046341; SET_dom_sf.
DR InterPro; IPR025785; SETD3.
DR InterPro; IPR044428; SETD3_SET.
DR Pfam; PF09273; Rubis-subs-bind; 1.
DR Pfam; PF00856; SET; 1.
DR SUPFAM; SSF81822; SSF81822; 1.
DR SUPFAM; SSF82199; SSF82199; 1.
DR PROSITE; PS51565; SAM_MT85_SETD3; 1.
DR PROSITE; PS50280; SET; 1.
PE 1: Evidence at protein level;
KW Actin-binding; Alternative splicing; Cytoplasm; Methyltransferase; Nucleus;
KW Phosphoprotein; Reference proteome; S-adenosyl-L-methionine; Transferase;
KW Ubl conjugation.
FT CHAIN 1..594
FT /note="Actin-histidine N-methyltransferase"
FT /id="PRO_0000254176"
FT DOMAIN 94..314
FT /note="SET"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00190"
FT REGION 1..22
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 551..594
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 7..22
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 556..584
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 75
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86TU7"
FT BINDING 104..106
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86TU7"
FT BINDING 254
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86TU7"
FT BINDING 275..279
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86TU7"
FT BINDING 325..327
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q86TU7"
FT VAR_SEQ 1..351
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_021194"
FT VAR_SEQ 1..128
FT /note="Missing (in isoform 2 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_021195"
FT VAR_SEQ 226..283
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_021196"
FT VAR_SEQ 284..290
FT /note="ITTGYNL -> VKISSWG (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_021197"
FT VAR_SEQ 291..594
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_021198"
FT CONFLICT 321
FT /note="F -> S (in Ref. 1; AAS82953 and 2; BAB27964)"
FT /evidence="ECO:0000305"
FT CONFLICT 460
FT /note="R -> Q (in Ref. 2; BAC27215)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 594 AA; 67176 MW; 67DA47889A5C9F55 CRC64;
MGKKSRVKTQ KSGTGATATV SPKEILNLTS ELLQKCSSPA PSPGKEWEEY TQIRALVEKI
RKKQKGLSVT FDGKREDYFP DLMKWASENG ASVEGFEMVN FKEEGFGLRA TRDIKAEELF
LWVPRKLLMT VESAKNSVLG PLYSQDRILQ AMGNIALAFH LLCERASPNS FWQPYIQTLP
SEYDTPLYFE EEEVRCLQST QAIHDVFSQY KNTARQYAYF YKVIQTHPHA NKLPLKESFT
YEDYRWAVSS VMTRQNQIPT EDGSRVTLAL IPLWDMCNHT NGLITTGYNL EDDRCECVAL
QDFQAGDQIY IFYGTRSNAE FVIHSGFFFD NNSHDRVKIK LGVSKSDRLY AMKAEVLARA
GIPTSSVFAL HSTEPPISAQ LLAFLRVFCM TEEELKEHLL GDSAIDRIFT LGNAEFPVSW
DNEVKLWTFL EDRASLLLKT YKTTIEEDKI VLKNPDLSVR ATMAIKLRLG EKEILEKAVK
SAAVNREYYR KHMEERAPLP RYEESDLGLL EGGVGDSRLP LVLRKLEEEA GVQESLSLTE
TVSKVKAAEN GLVNGENLIP NGTRSENESL SPEESENVTG EESSGSMAKV KERL
