ID   TRMB_MOUSE              Reviewed;         268 AA.
AC   Q9Z120; Q3TU83; Q921G5;
DT   20-JUN-2003, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-1999, sequence version 1.
DT   27-MAR-2024, entry version 161.
DE   RecName: Full=tRNA (guanine-N(7)-)-methyltransferase {ECO:0000255|HAMAP-Rule:MF_03055};
DE            EC=2.1.1.33 {ECO:0000255|HAMAP-Rule:MF_03055};
DE   AltName: Full=Methyltransferase-like protein 1 {ECO:0000255|HAMAP-Rule:MF_03055};
DE   AltName: Full=mRNA (guanine-N(7)-)-methyltransferase {ECO:0000255|HAMAP-Rule:MF_03055};
DE            EC=2.1.1.- {ECO:0000255|HAMAP-Rule:MF_03055};
DE   AltName: Full=miRNA (guanine-N(7)-)-methyltransferase {ECO:0000255|HAMAP-Rule:MF_03055};
DE            EC=2.1.1.- {ECO:0000255|HAMAP-Rule:MF_03055};
DE   AltName: Full=tRNA (guanine(46)-N(7))-methyltransferase {ECO:0000255|HAMAP-Rule:MF_03055};
DE   AltName: Full=tRNA(m7G46)-methyltransferase {ECO:0000255|HAMAP-Rule:MF_03055};
GN   Name=Mettl1 {ECO:0000312|MGI:MGI:1339986};
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].
RA   Tamura M., Nashimoto M., Kaspar R.L.;
RT   "Methyltransferase related protein.";
RL   Submitted (FEB-1999) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Extraembryonic tissue, and Placenta;
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 GENOMIC DNA].
RA   Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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   NUCLEOTIDE SEQUENCE [MRNA] OF 4-268.
RC   TISSUE=Brain;
RX   PubMed=10329009; DOI=10.1006/geno.1999.5780;
RA   Bahr A., Hankeln T., Fiedler T., Hegemann J., Schmidt E.R.;
RT   "Molecular analysis of METTL1, a novel human methyltransferase-like gene
RT   with a high degree of phylogenetic conservation.";
RL   Genomics 57:424-428(1999).
RN   [6]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain, Kidney, Liver, 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   [7]
RP   FUNCTION, AND PATHWAY.
RX   PubMed=29983320; DOI=10.1016/j.molcel.2018.06.001;
RA   Lin S., Liu Q., Lelyveld V.S., Choe J., Szostak J.W., Gregory R.I.;
RT   "Mettl1/Wdr4-mediated m7G tRNA methylome is required for normal mRNA
RT   translation and embryonic stem cell self-renewal and differentiation.";
RL   Mol. Cell 71:244-255(2018).
RN   [8]
RP   DISRUPTION PHENOTYPE.
RX   PubMed=34352206; DOI=10.1016/j.molcel.2021.07.003;
RA   Dai Z., Liu H., Liao J., Huang C., Ren X., Zhu W., Zhu S., Peng B., Li S.,
RA   Lai J., Liang L., Xu L., Peng S., Lin S., Kuang M.;
RT   "N7-Methylguanosine tRNA modification enhances oncogenic mRNA translation
RT   and promotes intrahepatic cholangiocarcinoma progression.";
RL   Mol. Cell 81:3339-3355(2021).
CC   -!- FUNCTION: Catalytic component of METTL1-WDR4 methyltransferase complex
CC       that mediates the formation of N(7)-methylguanine in a subset of RNA
CC       species, such as tRNAs, mRNAs and microRNAs (miRNAs) (By similarity).
CC       Catalyzes the formation of N(7)-methylguanine at position 46 (m7G46) in
CC       a large subset of tRNAs that contain the 5'-RAGGU-3' motif within the
CC       variable loop (By similarity). M7G46 interacts with C13-G22 in the D-
CC       loop to stabilize tRNA tertiary structure and protect tRNAs from decay
CC       (By similarity). Also acts as a methyltransferase for a subset of
CC       internal N(7)-methylguanine in mRNAs (PubMed:29983320). Internal N(7)-
CC       methylguanine methylation of mRNAs in response to stress promotes their
CC       relocalization to stress granules, thereby suppressing their
CC       translation (PubMed:29983320). Also methylates a specific subset of
CC       miRNAs, such as let-7 (By similarity). N(7)-methylguanine methylation
CC       of let-7 miRNA promotes let-7 miRNA processing by disrupting an
CC       inhibitory secondary structure within the primary miRNA transcript
CC       (pri-miRNA) (By similarity). Acts as a regulator of embryonic stem cell
CC       self-renewal and differentiation (PubMed:29983320). {ECO:0000255|HAMAP-
CC       Rule:MF_03055, ECO:0000269|PubMed:29983320}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=guanosine(46) in tRNA + S-adenosyl-L-methionine = N(7)-
CC         methylguanosine(46) in tRNA + S-adenosyl-L-homocysteine;
CC         Xref=Rhea:RHEA:42708, Rhea:RHEA-COMP:10188, Rhea:RHEA-COMP:10189,
CC         ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:74269,
CC         ChEBI:CHEBI:74480; EC=2.1.1.33; Evidence={ECO:0000255|HAMAP-
CC         Rule:MF_03055};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a guanosine in mRNA + S-adenosyl-L-methionine = an N(7)-
CC         methylguanosine in mRNA + S-adenosyl-L-homocysteine;
CC         Xref=Rhea:RHEA:60508, Rhea:RHEA-COMP:15584, Rhea:RHEA-COMP:15585,
CC         ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:74269,
CC         ChEBI:CHEBI:74480; Evidence={ECO:0000255|HAMAP-Rule:MF_03055};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60509;
CC         Evidence={ECO:0000255|HAMAP-Rule:MF_03055};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a guanosine in miRNA + S-adenosyl-L-methionine = an N(7)-
CC         methylguanosine in miRNA + S-adenosyl-L-homocysteine;
CC         Xref=Rhea:RHEA:60512, Rhea:RHEA-COMP:15587, Rhea:RHEA-COMP:15588,
CC         ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:74269,
CC         ChEBI:CHEBI:74480; Evidence={ECO:0000255|HAMAP-Rule:MF_03055};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:60513;
CC         Evidence={ECO:0000255|HAMAP-Rule:MF_03055};
CC   -!- PATHWAY: tRNA modification; N(7)-methylguanine-tRNA biosynthesis.
CC       {ECO:0000269|PubMed:29983320}.
CC   -!- SUBUNIT: Catalytic component of the METTL1-WDR4 complex, composed of
CC       METTL1 and WDR4. {ECO:0000255|HAMAP-Rule:MF_03055}.
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000255|HAMAP-Rule:MF_03055}.
CC   -!- DOMAIN: Upon tRNA-binding, the alphaC region transforms into a helix,
CC       which together with the alpha6 helix secures both ends of the tRNA
CC       variable loop (By similarity). The N-terminal disordered region is part
CC       of the catalytic pocket and essential for methyltransferase activity:
CC       upon S-adenosyl-L-methionine- and tRNA-binding, the N-terminal
CC       disordered region becomes ordered, sandwiched between the bound
CC       cofactor and the tRNA, and the WDR4 C-terminus attaches to the METTL1
CC       N-terminus to stabilize the bound tRNA together (By similarity).
CC       Together with WDR4, which also binds tRNAs, tRNAs undergo bending to
CC       facilitate G46 flipping into the catalytic pocket to be modified (By
CC       similarity). {ECO:0000255|HAMAP-Rule:MF_03055}.
CC   -!- PTM: Phosphorylation at Ser-21 by PKB/AKT1 inactivates its
CC       methyltransferase activity via a steric interference mechanism in the
CC       active site that locally disrupts the catalytic center (By similarity).
CC       Phosphorylation at Ser-21 does not affect the interaction with WDR4 (By
CC       similarity). {ECO:0000255|HAMAP-Rule:MF_03055}.
CC   -!- DISRUPTION PHENOTYPE: Conditional knockout in the liver impairs the
CC       formation of N(7)-methylguanine at position 46 (m7G46) in tRNAs and
CC       inhibits tumor development in an intrahepatic cholangiocarcinoma
CC       xenograph mouse model. {ECO:0000269|PubMed:34352206}.
CC   -!- MISCELLANEOUS: In the context of cancer, overexpression of the METTL1-
CC       WDR4 methyltransferase complex promotes cancer progression by driving
CC       oncogenic transformation (PubMed:34352206). Drives oncogenesis by
CC       mediating the formation of N(7)-methylguanine at position 46 (m7G46) in
CC       some tRNAs, in particular Arg-TCT-4-1 (TRR-TCT4-1), leading to
CC       increased translation of mRNAs, including cell cycle regulators that
CC       are enriched in the corresponding AGA codon (PubMed:34352206).
CC       {ECO:0000269|PubMed:34352206}.
CC   -!- SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase
CC       superfamily. TrmB family. {ECO:0000255|HAMAP-Rule:MF_03055}.
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DR   EMBL; AB023619; BAA75230.1; -; mRNA.
DR   EMBL; AK160914; BAE36088.1; -; mRNA.
DR   EMBL; CH466578; EDL24462.1; -; Genomic_DNA.
DR   EMBL; BC012649; AAH12649.1; -; mRNA.
DR   EMBL; Y18644; CAA77240.1; -; mRNA.
DR   CCDS; CCDS24223.1; -.
DR   RefSeq; NP_034922.1; NM_010792.1.
DR   AlphaFoldDB; Q9Z120; -.
DR   SMR; Q9Z120; -.
DR   BioGRID; 201404; 15.
DR   STRING; 10090.ENSMUSP00000006915; -.
DR   iPTMnet; Q9Z120; -.
DR   PhosphoSitePlus; Q9Z120; -.
DR   SwissPalm; Q9Z120; -.
DR   EPD; Q9Z120; -.
DR   MaxQB; Q9Z120; -.
DR   PaxDb; 10090-ENSMUSP00000006915; -.
DR   PeptideAtlas; Q9Z120; -.
DR   ProteomicsDB; 258854; -.
DR   Pumba; Q9Z120; -.
DR   Antibodypedia; 16399; 206 antibodies from 29 providers.
DR   DNASU; 17299; -.
DR   Ensembl; ENSMUST00000006915.14; ENSMUSP00000006915.8; ENSMUSG00000006732.15.
DR   GeneID; 17299; -.
DR   KEGG; mmu:17299; -.
DR   UCSC; uc007hhq.1; mouse.
DR   AGR; MGI:1339986; -.
DR   CTD; 4234; -.
DR   MGI; MGI:1339986; Mettl1.
DR   VEuPathDB; HostDB:ENSMUSG00000006732; -.
DR   eggNOG; KOG3115; Eukaryota.
DR   GeneTree; ENSGT00390000017840; -.
DR   HOGENOM; CLU_050910_3_0_1; -.
DR   InParanoid; Q9Z120; -.
DR   OMA; LPNYFAK; -.
DR   OrthoDB; 116813at2759; -.
DR   PhylomeDB; Q9Z120; -.
DR   TreeFam; TF314083; -.
DR   UniPathway; UPA00989; -.
DR   BioGRID-ORCS; 17299; 17 hits in 80 CRISPR screens.
DR   PRO; PR:Q9Z120; -.
DR   Proteomes; UP000000589; Chromosome 10.
DR   RNAct; Q9Z120; Protein.
DR   Bgee; ENSMUSG00000006732; Expressed in lacrimal gland and 213 other cell types or tissues.
DR   ExpressionAtlas; Q9Z120; baseline and differential.
DR   GO; GO:0005829; C:cytosol; ISO:MGI.
DR   GO; GO:0005730; C:nucleolus; ISO:MGI.
DR   GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0106143; C:tRNA (m7G46) methyltransferase complex; ISS:UniProtKB.
DR   GO; GO:0043527; C:tRNA methyltransferase complex; IBA:GO_Central.
DR   GO; GO:0160090; F:internal mRNA (guanine-N7-)-methyltransferase activity; ISO:MGI.
DR   GO; GO:0008176; F:tRNA (guanine(46)-N7)-methyltransferase activity; ISS:UniProtKB.
DR   GO; GO:0000049; F:tRNA binding; IEA:UniProtKB-UniRule.
DR   GO; GO:0036265; P:RNA (guanine-N7)-methylation; ISO:MGI.
DR   GO; GO:0106004; P:tRNA (guanine-N7)-methylation; ISS:UniProtKB.
DR   GO; GO:0030488; P:tRNA methylation; IBA:GO_Central.
DR   GO; GO:0006400; P:tRNA modification; ISS:UniProtKB.
DR   GO; GO:0036416; P:tRNA stabilization; ISO:MGI.
DR   Gene3D; 3.40.50.150; Vaccinia Virus protein VP39; 1.
DR   HAMAP; MF_03055; tRNA_methyltr_TrmB_euk; 1.
DR   InterPro; IPR029063; SAM-dependent_MTases_sf.
DR   InterPro; IPR025763; Trm8_euk.
DR   InterPro; IPR003358; tRNA_(Gua-N-7)_MeTrfase_Trmb.
DR   NCBIfam; TIGR00091; tRNA (guanosine(46)-N7)-methyltransferase TrmB; 1.
DR   PANTHER; PTHR23417; 3-DEOXY-D-MANNO-OCTULOSONIC-ACID TRANSFERASE/TRNA GUANINE-N 7 - -METHYLTRANSFERASE; 1.
DR   PANTHER; PTHR23417:SF16; TRNA (GUANINE-N(7)-)-METHYLTRANSFERASE; 1.
DR   Pfam; PF02390; Methyltransf_4; 1.
DR   SUPFAM; SSF53335; S-adenosyl-L-methionine-dependent methyltransferases; 1.
DR   PROSITE; PS51625; SAM_MT_TRMB; 1.
DR   Genevisible; Q9Z120; MM.
PE   1: Evidence at protein level;
KW   Methyltransferase; Nucleus; Phosphoprotein; Reference proteome;
KW   RNA-binding; S-adenosyl-L-methionine; Transferase; tRNA processing;
KW   tRNA-binding.
FT   CHAIN           1..268
FT                   /note="tRNA (guanine-N(7)-)-methyltransferase"
FT                   /id="PRO_0000171432"
FT   REGION          1..21
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          158..166
FT                   /note="AlphaC helix"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03055"
FT   REGION          232..240
FT                   /note="Alpha6 helix"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03055"
FT   ACT_SITE        157
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03055"
FT   BINDING         78
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03055"
FT   BINDING         101
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03055"
FT   BINDING         103
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03055"
FT   BINDING         134
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03055"
FT   BINDING         135
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03055"
FT   BINDING         154
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03055"
FT   BINDING         232
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03055"
FT   BINDING         234
FT                   /ligand="S-adenosyl-L-methionine"
FT                   /ligand_id="ChEBI:CHEBI:59789"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03055"
FT   MOD_RES         21
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_03055"
FT   CONFLICT        52
FT                   /note="I -> N (in Ref. 4; AAH12649)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        56
FT                   /note="S -> N (in Ref. 4; AAH12649)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        213
FT                   /note="R -> C (in Ref. 4; AAH12649)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   268 AA;  30603 MW;  1DAE1EEAA4A07627 CRC64;
     MMAGAEAPQP QKRYYRQRAH SNPMADHTLR YPVKPEEMDW SELYPEFFAP LIQNKSHDDP
     KDEKEKHSGA QVEFADIGCG YGGLLVALSP LFPDTLILGL EIRVKVSDYV QDRIRALRAA
     PGGGFQNIAC LRSNAMKHLP NFFRKGQLAK MFFLFPDPHF KRTKHKWRII SPTLLAEYAY
     VLRVGGLVYT VTDVPELHEW MCTHFEEHPL FERVPLEELS EDPIVEHLGS STEEGKKVLR
     NGGKNFPAVF RRIQDPLLQA VTPNPTLP
//