METL8_MOUSE
ID METL8_MOUSE Reviewed; 281 AA.
AC A2AUU0; A2AUU3; Q2XV35; Q2XV36; Q4FCR9; Q4FCS0; Q6PEN9; Q99KI7;
DT 13-NOV-2007, integrated into UniProtKB/Swiss-Prot.
DT 13-NOV-2007, sequence version 2.
DT 03-AUG-2022, entry version 96.
DE RecName: Full=tRNA N(3)-methylcytidine methyltransferase METTL8, mitochondrial {ECO:0000305};
DE EC=2.1.1.- {ECO:0000250|UniProtKB:Q9H825};
DE AltName: Full=Methyltransferase-like protein 8 {ECO:0000305};
DE AltName: Full=Tension-induced/inhibited protein {ECO:0000303|PubMed:18710950};
DE AltName: Full=mRNA N(3)-methylcytidine methyltransferase METTL8 {ECO:0000305};
DE EC=2.1.1.- {ECO:0000305|PubMed:28655767};
DE Flags: Precursor;
GN Name=Mettl8 {ECO:0000303|PubMed:28655767, ECO:0000312|MGI:MGI:2385142};
GN Synonyms=Tip {ECO:0000303|PubMed:18710950};
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] (ISOFORMS 2; 4 AND 5), FUNCTION, SUBCELLULAR
RP LOCATION, TISSUE SPECIFICITY, AND INDUCTION.
RC STRAIN=CD-1;
RX PubMed=15992539; DOI=10.1016/j.devcel.2005.04.015;
RA Jakkaraju S., Zhe X., Pan D., Choudhury R., Schuger L.;
RT "TIPs are tension-responsive proteins involved in myogenic versus
RT adipogenic differentiation.";
RL Dev. Cell 9:39-49(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 6), FUNCTION, INTERACTION WITH
RP EP300, AND ALTERNATIVE SPLICING (ISOFORMS 7; 8 AND 9).
RC STRAIN=NIH Swiss;
RX PubMed=18710950; DOI=10.1128/mcb.00333-08;
RA Badri K.R., Zhou Y., Dhru U., Aramgam S., Schuger L.;
RT "Effects of the SANT domain of tension-induced/inhibited proteins (TIPs),
RT novel partners of the histone acetyltransferase p300, on p300 activity and
RT TIP-6-induced adipogenesis.";
RL Mol. Cell. Biol. 28:6358-6372(2008).
RN [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 49-281 (ISOFORM 3).
RC STRAIN=FVB/N; TISSUE=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 [5]
RP FUNCTION, CATALYTIC ACTIVITY, AND DISRUPTION PHENOTYPE.
RX PubMed=28655767; DOI=10.1074/jbc.m117.798298;
RA Xu L., Liu X., Sheng N., Oo K.S., Liang J., Chionh Y.H., Xu J., Ye F.,
RA Gao Y.G., Dedon P.C., Fu X.Y.;
RT "Three distinct 3-methylcytidine (m3C) methyltransferases modify tRNA and
RT mRNA in mice and humans.";
RL J. Biol. Chem. 292:14695-14703(2017).
CC -!- FUNCTION: Mitochondrial S-adenosyl-L-methionine-dependent
CC methyltransferase that mediates N(3)-methylcytidine modification of
CC residue 32 of the tRNA anticodon loop of mitochondrial tRNA(Ser)(UCN)
CC and tRNA(Thr) (By similarity). N(3)-methylcytidine methylation
CC modification regulates mitochondrial translation efficiency and is
CC required for activity of the respiratory chain (By similarity). N(3)-
CC methylcytidine methylation of mitochondrial tRNA(Ser)(UCN) requires the
CC formation of N(6)-dimethylallyladenosine(37) (i6A37) by TRIT1 as
CC prerequisite (By similarity). May also mediate N(3)-methylcytidine
CC modification of mRNAs (PubMed:28655767). The existence of N(3)-
CC methylcytidine modification on mRNAs is however unclear, and additional
CC evidences are required to confirm the role of the N(3)-methylcytidine-
CC specific mRNA methyltransferase activity of METTL8 in vivo (By
CC similarity). {ECO:0000250|UniProtKB:Q9H825,
CC ECO:0000269|PubMed:28655767}.
CC -!- FUNCTION: [Isoform 5]: Overexpression in lung progenitor cells
CC stimulates smooth muscle-specific gene expression and suppresses
CC adipogenic gene expression. {ECO:0000269|PubMed:15992539}.
CC -!- FUNCTION: [Isoform 4]: Stimulates adipogenesis.
CC {ECO:0000269|PubMed:18710950}.
CC -!- FUNCTION: [Isoform 7]: Stimulates adipogenesis.
CC {ECO:0000269|PubMed:18710950}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cytidine(32) in tRNA(Ser) + S-adenosyl-L-methionine = H(+) +
CC N(3)-methylcytidine(32) in tRNA(Ser) + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:50956, Rhea:RHEA-COMP:12849, Rhea:RHEA-COMP:12851,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:74894, ChEBI:CHEBI:82748;
CC Evidence={ECO:0000250|UniProtKB:Q9H825};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50957;
CC Evidence={ECO:0000250|UniProtKB:Q9H825};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cytidine(32) in tRNA(Thr) + S-adenosyl-L-methionine = H(+) +
CC N(3)-methylcytidine(32) in tRNA(Thr) + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:50960, Rhea:RHEA-COMP:12850, Rhea:RHEA-COMP:12852,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:74894, ChEBI:CHEBI:82748;
CC Evidence={ECO:0000250|UniProtKB:Q9H825};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50961;
CC Evidence={ECO:0000250|UniProtKB:Q9H825};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a cytidine in mRNA + S-adenosyl-L-methionine = an N(3)-
CC methylcytidine in mRNA + H(+) + S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:60916, Rhea:RHEA-COMP:15145, Rhea:RHEA-COMP:15713,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:74894, ChEBI:CHEBI:82748;
CC Evidence={ECO:0000305|PubMed:28655767};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60917;
CC Evidence={ECO:0000305|PubMed:28655767};
CC -!- SUBUNIT: Interacts with EP300. {ECO:0000269|PubMed:18710950}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:Q9H825}.
CC Cytoplasm {ECO:0000305|PubMed:15992539}. Nucleus
CC {ECO:0000305|PubMed:15992539}. Note=Mitochondrial protein (By
CC similarity). The cytoplasmic or nuclear localization observed by some
CC groups is either the result of an incorrect localization caused by N-
CC terminal tagging that interferes with mitochondrial targeting, or
CC splice isoforms that lack the N-terminal mitochondrial transit sequence
CC (By similarity). {ECO:0000250|UniProtKB:Q9H825}.
CC -!- SUBCELLULAR LOCATION: [Isoform 5]: Nucleus
CC {ECO:0000269|PubMed:15992539}. Note=Isoform 5 localizes to the nucleus
CC upon cell stretch in embryonic lung progenitor cells.
CC {ECO:0000269|PubMed:15992539}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=9;
CC Name=1;
CC IsoId=A2AUU0-1; Sequence=Displayed;
CC Name=2; Synonyms=TIP-2 {ECO:0000303|PubMed:18710950};
CC IsoId=A2AUU0-2; Sequence=VSP_029516;
CC Name=3; Synonyms=TIP-4 {ECO:0000303|PubMed:18710950};
CC IsoId=A2AUU0-3; Sequence=VSP_029517;
CC Name=4; Synonyms=TIP-3 {ECO:0000303|PubMed:18710950};
CC IsoId=A2AUU0-4; Sequence=VSP_029518;
CC Name=5; Synonyms=TIP-1 {ECO:0000303|PubMed:18710950};
CC IsoId=A2AUU0-5; Sequence=VSP_029515;
CC Name=6; Synonyms=TIP-5 {ECO:0000303|PubMed:18710950};
CC IsoId=A2AUU0-6; Sequence=VSP_037111, VSP_029517;
CC Name=7; Synonyms=TIP-6 {ECO:0000303|PubMed:18710950};
CC IsoId=A2AUU0-7; Sequence=Not described;
CC Name=8; Synonyms=TIP-7 {ECO:0000303|PubMed:18710950};
CC IsoId=A2AUU0-8; Sequence=Not described;
CC Name=9; Synonyms=TIP-8 {ECO:0000303|PubMed:18710950};
CC IsoId=A2AUU0-9; Sequence=Not described;
CC -!- TISSUE SPECIFICITY: [Isoform 2]: Absent in embryonic lung but is
CC induced in a fibroblast cell line by stretch.
CC {ECO:0000269|PubMed:15992539}.
CC -!- TISSUE SPECIFICITY: [Isoform 4]: Expressed in undifferentiated
CC progenitor cells, while its expression is inhibited by stretch.
CC {ECO:0000269|PubMed:15992539}.
CC -!- TISSUE SPECIFICITY: [Isoform 5]: Absent in undifferentiated embryonic
CC lung mesenchymal cells, but expression is induced by stretch.
CC {ECO:0000269|PubMed:15992539}.
CC -!- TISSUE SPECIFICITY: [Isoform 7]: Expressed in mature adipose tissue.
CC {ECO:0000269|PubMed:15992539}.
CC -!- INDUCTION: [Isoform 5]: Induced in stretched embryonic lung mesenchymal
CC cells. {ECO:0000269|PubMed:15992539}.
CC -!- DISRUPTION PHENOTYPE: Mice were born with normal Mendelian ratio
CC without developmental defects (PubMed:28655767). Cells show reduced
CC N(3)-methylcytidine modification in mRNAs (PubMed:28655767).
CC {ECO:0000269|PubMed:28655767}.
CC -!- SIMILARITY: Belongs to the methyltransferase superfamily. METL family.
CC {ECO:0000305}.
CC -!- CAUTION: According to some authors, contains a SANT domain but this
CC domain is not detected by any prediction tool.
CC {ECO:0000305|PubMed:15992539, ECO:0000305|PubMed:18710950}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH04636.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=AAH57960.1; Type=Miscellaneous discrepancy; Note=Sequence differs from the displayed sequence in the N-terminal region.; Evidence={ECO:0000305};
CC Sequence=AAZ04166.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=AAZ04167.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; DQ093357; AAZ04166.1; ALT_INIT; mRNA.
DR EMBL; DQ093358; AAZ04167.1; ALT_INIT; mRNA.
DR EMBL; DQ230973; ABB54392.1; -; mRNA.
DR EMBL; DQ230974; ABB54393.1; -; mRNA.
DR EMBL; AL929228; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC004636; AAH04636.1; ALT_INIT; mRNA.
DR EMBL; BC057960; AAH57960.1; ALT_SEQ; mRNA.
DR CCDS; CCDS50600.1; -. [A2AUU0-3]
DR RefSeq; NP_001103982.1; NM_001110512.1. [A2AUU0-6]
DR RefSeq; NP_663499.2; NM_145524.3. [A2AUU0-3]
DR RefSeq; XP_006499258.1; XM_006499195.3.
DR AlphaFoldDB; A2AUU0; -.
DR SMR; A2AUU0; -.
DR STRING; 10090.ENSMUSP00000107804; -.
DR PhosphoSitePlus; A2AUU0; -.
DR jPOST; A2AUU0; -.
DR MaxQB; A2AUU0; -.
DR PaxDb; A2AUU0; -.
DR PRIDE; A2AUU0; -.
DR ProteomicsDB; 295546; -. [A2AUU0-1]
DR ProteomicsDB; 295547; -. [A2AUU0-2]
DR ProteomicsDB; 295548; -. [A2AUU0-3]
DR ProteomicsDB; 295549; -. [A2AUU0-4]
DR ProteomicsDB; 295550; -. [A2AUU0-5]
DR ProteomicsDB; 295551; -. [A2AUU0-6]
DR Antibodypedia; 49777; 14 antibodies from 7 providers.
DR DNASU; 228019; -.
DR Ensembl; ENSMUST00000112179; ENSMUSP00000107800; ENSMUSG00000041975. [A2AUU0-5]
DR Ensembl; ENSMUST00000112186; ENSMUSP00000107804; ENSMUSG00000041975. [A2AUU0-3]
DR Ensembl; ENSMUST00000121586; ENSMUSP00000113642; ENSMUSG00000041975. [A2AUU0-1]
DR Ensembl; ENSMUST00000148876; ENSMUSP00000115855; ENSMUSG00000041975. [A2AUU0-2]
DR GeneID; 228019; -.
DR KEGG; mmu:228019; -.
DR UCSC; uc008jzw.3; mouse. [A2AUU0-6]
DR UCSC; uc008jzx.3; mouse. [A2AUU0-3]
DR CTD; 79828; -.
DR MGI; MGI:2385142; Mettl8.
DR VEuPathDB; HostDB:ENSMUSG00000041975; -.
DR eggNOG; KOG2361; Eukaryota.
DR GeneTree; ENSGT00940000159683; -.
DR HOGENOM; CLU_029724_5_0_1; -.
DR InParanoid; A2AUU0; -.
DR OMA; CCLSENF; -.
DR OrthoDB; 987359at2759; -.
DR PhylomeDB; A2AUU0; -.
DR TreeFam; TF323232; -.
DR BioGRID-ORCS; 228019; 1 hit in 71 CRISPR screens.
DR ChiTaRS; Mettl8; mouse.
DR PRO; PR:A2AUU0; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; A2AUU0; protein.
DR Bgee; ENSMUSG00000041975; Expressed in ileal epithelium and 242 other tissues.
DR ExpressionAtlas; A2AUU0; baseline and differential.
DR Genevisible; A2AUU0; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0004402; F:histone acetyltransferase activity; IDA:MGI.
DR GO; GO:0008174; F:mRNA methyltransferase activity; IMP:MGI.
DR GO; GO:0052735; F:tRNA (cytosine-3-)-methyltransferase activity; ISS:UniProtKB.
DR GO; GO:0045444; P:fat cell differentiation; IDA:MGI.
DR GO; GO:0016573; P:histone acetylation; IDA:MGI.
DR GO; GO:0080009; P:mRNA methylation; IMP:MGI.
DR GO; GO:0070131; P:positive regulation of mitochondrial translation; ISS:UniProtKB.
DR GO; GO:0007519; P:skeletal muscle tissue development; IDA:MGI.
DR GO; GO:0106217; P:tRNA C3-cytosine methylation; ISS:UniProtKB.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR041698; Methyltransf_25.
DR InterPro; IPR026113; MeTrfase.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR PANTHER; PTHR22809; PTHR22809; 1.
DR Pfam; PF13649; Methyltransf_25; 1.
DR PIRSF; PIRSF037755; Mettl2_prd; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cytoplasm; Isopeptide bond; Methyltransferase;
KW Mitochondrion; Nucleus; Reference proteome; S-adenosyl-L-methionine;
KW Transferase; Transit peptide; tRNA processing; Ubl conjugation.
FT TRANSIT 1..22
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 23..281
FT /note="tRNA N(3)-methylcytidine methyltransferase METTL8,
FT mitochondrial"
FT /evidence="ECO:0000255"
FT /id="PRO_0000311292"
FT REGION 139..180
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 89
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q8TCB7"
FT BINDING 93
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q8TCB7"
FT BINDING 194
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q8TCB7"
FT BINDING 220
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q8TCB7"
FT BINDING 246
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:Q8TCB7"
FT CROSSLNK 80
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250|UniProtKB:Q9H825"
FT VAR_SEQ 79..154
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:18710950"
FT /id="VSP_037111"
FT VAR_SEQ 193..281
FT /note="VGCGAGNSVFPILNTLQNIPGSFLYCCDFASEAVELVKSHESYSEAQCSAFI
FT HDVCDDGLAYPFPDGILDVVLLVFVLSSIHPDRALFI -> EHSRILSLLLRLCL (in
FT isoform 5)"
FT /evidence="ECO:0000303|PubMed:15992539"
FT /id="VSP_029515"
FT VAR_SEQ 278..281
FT /note="ALFI -> QVPPCLPNRTCDFYKMSQPPGRGYRPA (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:15992539"
FT /id="VSP_029516"
FT VAR_SEQ 278..281
FT /note="ALFI -> MQAVAHRLSRLLKPGGMLLFRDHGRYDNAQLRFKKGRCLSENFY
FT VRGDGTRAYFFTKGEIRRMFCEAGLHEKQNLVDHRLQVNRKKQVQMHRVWIQGKFQKPS
FT PWTPQSGN (in isoform 3 and isoform 6)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:18710950"
FT /id="VSP_029517"
FT VAR_SEQ 278..281
FT /note="ALFI -> MQAVAHRLSRLLKPGGMLLFRDHGRYDNAQLRFKKGRCLSENFY
FT VRGDGPELISLQKGKSAVCSARLDYTKSKIWLIIACK (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:15992539"
FT /id="VSP_029518"
FT CONFLICT 91
FT /note="I -> T (in Ref. 2; ABB54392 and 4; AAH04636/
FT AAH57960)"
FT /evidence="ECO:0000305"
FT CONFLICT 161
FT /note="R -> W (in Ref. 1; AAZ04166/AAZ04167, 2; ABB54392/
FT ABB54393 and 4; AAH04636/AAH57960)"
FT /evidence="ECO:0000305"
FT CONFLICT 233
FT /note="E -> K (in Ref. 1; AAZ04167, 2; ABB54392/ABB54393
FT and 4; AAH04636/AAH57960)"
FT /evidence="ECO:0000305"
FT CONFLICT 238
FT /note="A -> T (in Ref. 1; AAZ04167, 2; ABB54392/ABB54393
FT and 4; AAH04636/AAH57960)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 281 AA; 31670 MW; 2B6DD620DA56FBFB CRC64;
MNVIWRSCIC RLRQGKVPHR CQSGVHPVAP LGSRILTDPA KVFEHNMWDH MQWSKEEEDA
ARKKVEENSA TRVAPEEQVK FESDANKYWD IFYQTHKNKF FKNRNWLLRE FPEILPVNQN
TKEKVGESSW DQVGSSISRT QGTETHCQES FVSPEPGSRG RSAPDPDLEE YSKGPGKTEP
FPGSNATFRI LEVGCGAGNS VFPILNTLQN IPGSFLYCCD FASEAVELVK SHESYSEAQC
SAFIHDVCDD GLAYPFPDGI LDVVLLVFVL SSIHPDRALF I
