{"gene":"TRMT11","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2005,"finding":"Yeast Trm11p (ortholog of human TRMT11) is the catalytic subunit of the tRNA m2G10 methyltransferase, which requires Trm112p as an obligate partner subunit; together they catalyze formation of N2-methylguanosine at position 10 in tRNA, using S-adenosylmethionine as methyl donor.","method":"Genetic deletion, in vivo co-immunoprecipitation, in vitro methyltransferase assay with purified complex","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — enzymatic activity demonstrated in vitro, catalytic subunit assignment confirmed by deletion mutants and co-IP, replicated across multiple subsequent studies","pmids":["15899842"],"is_preprint":false},{"year":2005,"finding":"TRM11 genetically interacts with TRM1 (the m2,2G26 methyltransferase), suggesting that absence of m2G10 and m2,2G26 together affects tRNA metabolism or function.","method":"Genetic epistasis / double-deletion analysis in yeast","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic interaction observed in single study, no molecular mechanism elucidated beyond the phenotypic observation","pmids":["15899842"],"is_preprint":false},{"year":2009,"finding":"Active yeast Trm11-Trm112 complex was reconstituted in a wheat germ cell-free translation system, confirming that co-expression of both subunits is sufficient to reconstitute m2G10 methyltransferase activity.","method":"Cell-free reconstitution (wheat germ cell-free translation) followed by methyltransferase activity assay","journal":"Nucleic acids symposium series","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution of activity, but single study with limited methodological detail in abstract","pmids":["19749381"],"is_preprint":false},{"year":2011,"finding":"Trm112 activates Trm11 (as well as Trm9 and Mtq2) through a common structural mechanism: the Mtq2-Trm112 crystal structure, validated by site-directed mutagenesis and in vivo functional experiments, serves as a model for all three Trm112-methyltransferase complexes including Trm11-Trm112.","method":"X-ray crystallography of Mtq2-Trm112 complex, site-directed mutagenesis, in vivo functional assays, structural modeling of Trm11-Trm112","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis plus in vivo functional validation in one study; Trm11-Trm112 inferred by structural modeling with experimental support","pmids":["21478168"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of multiple Trm112-methyltransferase complexes reveal structural plasticity: Trm112 uses a similar interaction surface to activate Trm9, Trm11, Bud23, and Mtq2 despite those partners sharing less than 20% sequence identity.","method":"X-ray crystallography of Trm9-Trm112 complex; comparative structural analysis of known Trm112-MTase crystal structures","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with structure-function analysis; Trm11-Trm112 interaction mode inferred from comparative structural data with strong supporting evidence across multiple complexes","pmids":["26438534"],"is_preprint":false},{"year":2017,"finding":"Trm112 activates Trm11 enzymatic activity by influencing S-adenosyl-L-methionine (SAM) binding and by contributing to tRNA substrate binding; hydrogen-deuterium exchange mass spectrometry showed the Trm11-Trm112 interaction relies on the same molecular interface as other Trm112-methyltransferase complexes, meaning all Trm112-dependent methyltransferases compete for the same binding surface on Trm112.","method":"Enzymatic activity assays (in vitro methyltransferase), hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS)","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay plus orthogonal HDX-MS structural probing, mechanistic dissection of SAM-binding and tRNA-binding contributions, single lab but two orthogonal methods","pmids":["27986851"],"is_preprint":false},{"year":2019,"finding":"Archaeal Trm11 (ortholog) from Thermococcus kodakarensis is required for formation of m2G10 and m2,2G10 in tRNA; deletion of trm11 results in poor growth at 95°C, indicating the m2,2G10 modification contributes to tRNA stabilization at high temperatures.","method":"Gene deletion in T. kodakarensis, LC-MS tRNA modification analysis, growth phenotype assay at high temperature","journal":"Journal of bacteriology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean gene deletion with defined molecular (LC-MS modification loss) and physiological phenotype, single lab","pmids":["31405913"],"is_preprint":false},{"year":2020,"finding":"Crystal structures of the Archaeoglobus fulgidus Trm11-Trm112 complex and of Trm11 alone (or bound to sinefungin inhibitor) reveal the molecular basis of Trm112-dependent activation: AfTrm11 is active as a single protein but its enzymatic activity is strongly enhanced by AfTrm112, and the interaction resembles eukaryotic Trm11-Trm112 complexes.","method":"X-ray crystallography, in vitro methyltransferase activity assays comparing Trm11 alone vs. Trm11-Trm112 complex","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures (multiple forms) plus quantitative in vitro activity assays, mechanistic conclusion well supported by two orthogonal methods in single rigorous study","pmids":["33035335"],"is_preprint":false},{"year":2021,"finding":"Human TRMT112 (the activator hub) interacts with TRMT11 along with six other methyltransferases; TRMT112 stabilizes all partner MTases including TRMT11 in cells, and single amino acid mutations on the TRMT112 surface reveal differential binding contributions across partners.","method":"SILAC co-immunoprecipitation screen (pulldown of TRMT112), western blot stability assays, site-directed mutagenesis of TRMT112","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — quantitative proteomics pulldown (SILAC) plus mutagenesis and stability assays, single lab, interaction and stabilization function established for TRMT11 specifically","pmids":["34948388"],"is_preprint":false},{"year":2022,"finding":"The eukaryotic Trm11-Trm112 complex requires specific tRNA structural elements for methylation: mature tRNA (not precursor) with CCA terminus, a regular-size variable region, G10-C25 base pair, and anticodon-loop contacts are needed; U38 in tRNAAla and U32-A38 base pair in tRNACys act as negative determinants.","method":"In vitro methyltransferase assays with 60 tRNA transcript variants; purification of tRNAValAAC1 from wild-type and trm11 deletion yeast strains","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic in vitro substrate specificity mapping with 60 variants plus in vivo confirmation using deletion strains, comprehensive mechanistic substrate mapping","pmids":["35409407"],"is_preprint":false},{"year":2023,"finding":"Human TRMT11, identified as a direct partner of TRMT112 in intact human cells, is an active N2-methylguanosine (m2G) methyltransferase that methylates position 10 of tRNAs; combined loss of TRMT11 and THUMPD3 impairs optimal protein synthesis and cell proliferation.","method":"Co-immunoprecipitation of TRMT112 interactome in human cells, LC-MS/MS tRNA modification analysis, siRNA knockdown with translation and proliferation assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — enzymatic activity demonstrated biochemically in human cells, substrate (tRNA position 10) confirmed by mass spectrometry, functional consequence of loss shown by two orthogonal cellular assays","pmids":["37283053"],"is_preprint":false},{"year":2023,"finding":"Yeast Trm11 incorporates N2-methylguanosine (m2G) into mRNA codons in addition to tRNA; m2G introduced into mRNA codons impedes amino acid addition by the ribosome in a position-dependent manner, as shown in a reconstituted translation system.","method":"LC-MS/MS mRNA modification profiling, mRNA purification, reconstituted in vitro translation assay with modified mRNA substrates","journal":"RSC chemical biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution of translation inhibition and LC-MS/MS modification detection, but mRNA methylation by Trm11 is a novel and unexpected finding from a single study","pmids":["37181630"],"is_preprint":false}],"current_model":"TRMT11 (yeast Trm11) is the catalytic subunit of a two-subunit tRNA methyltransferase that, together with its obligate activator partner TRMT112, catalyzes S-adenosylmethionine-dependent N2-methylation of guanosine at position 10 in tRNA; TRMT112 enhances enzymatic activity by promoting SAM binding and tRNA substrate engagement through a conserved protein–protein interface, and mature tRNA with a CCA terminus, G10-C25 base pair, and appropriate anticodon-loop contacts are required as substrate determinants."},"narrative":{"mechanistic_narrative":"TRMT11 (yeast Trm11) is the catalytic subunit of a tRNA methyltransferase that installs N2-methylguanosine at position 10 (m2G10) using S-adenosylmethionine as methyl donor, a reaction strictly dependent on the obligate partner subunit TRMT112 [PMID:15899842]. TRMT112 activates TRMT11 through a conserved protein–protein interface shared across the Trm112-dependent methyltransferase family, enhancing catalysis by promoting SAM binding and contributing to tRNA substrate engagement; this same surface is used competitively by all of TRMT112's methyltransferase partners [PMID:27986851, PMID:33035335]. In human cells TRMT11 is a direct TRMT112 interactor and an active m2G methyltransferase acting on tRNA position 10, and TRMT112 stabilizes TRMT11 protein in cells [PMID:34948388, PMID:37283053]. Substrate recognition requires mature tRNA bearing a CCA terminus, a G10-C25 base pair, a regular variable region, and appropriate anticodon-loop contacts, with specific anticodon-loop features acting as negative determinants [PMID:35409407]. Functionally, combined loss of TRMT11 and THUMPD3 impairs optimal protein synthesis and cell proliferation, linking the modification to translational fidelity [PMID:37283053].","teleology":[{"year":2005,"claim":"Established the enzymatic identity of TRMT11 by showing the yeast ortholog is the catalytic subunit of the m2G10 tRNA methyltransferase, requiring Trm112 as an obligate partner.","evidence":"Genetic deletion, in vivo co-IP, and in vitro methyltransferase assay with purified complex in yeast","pmids":["15899842"],"confidence":"High","gaps":["Structural basis of the Trm11-Trm112 interaction not defined","Substrate determinants on tRNA not mapped"]},{"year":2005,"claim":"Linked m2G10 to broader tRNA modification networks via genetic interaction between TRM11 and the m2,2G26 methyltransferase TRM1.","evidence":"Genetic epistasis / double-deletion analysis in yeast","pmids":["15899842"],"confidence":"Medium","gaps":["No molecular mechanism for the interaction beyond phenotype","Functional consequence of combined modification loss unresolved"]},{"year":2009,"claim":"Confirmed that co-expression of both subunits is sufficient to reconstitute active enzyme, supporting the two-subunit model.","evidence":"Wheat germ cell-free reconstitution followed by methyltransferase activity assay","pmids":["19749381"],"confidence":"Medium","gaps":["Limited methodological detail","Quantitative kinetics not reported"]},{"year":2011,"claim":"Defined Trm112 as a common structural activator across multiple methyltransferases, providing a structural model for Trm11-Trm112 activation.","evidence":"X-ray crystallography of Mtq2-Trm112, site-directed mutagenesis, in vivo functional assays, and structural modeling","pmids":["21478168"],"confidence":"High","gaps":["Trm11-Trm112 interface inferred by modeling rather than direct structure","Catalytic mechanism not addressed"]},{"year":2015,"claim":"Demonstrated that Trm112 uses one conserved surface to activate diverse partners despite low sequence identity, framing Trm11 as one of several competing clients.","evidence":"X-ray crystallography of Trm9-Trm112 and comparative structural analysis of Trm112-MTase complexes","pmids":["26438534"],"confidence":"High","gaps":["Direct Trm11-Trm112 structure still not solved at this point","Competition dynamics in vivo unquantified"]},{"year":2017,"claim":"Dissected the activation mechanism, showing Trm112 enhances Trm11 activity via effects on SAM binding and tRNA engagement through a shared interface used by all partners.","evidence":"In vitro methyltransferase assays plus hydrogen-deuterium exchange mass spectrometry","pmids":["27986851"],"confidence":"High","gaps":["Atomic-resolution Trm11-Trm112 structure not yet available","Kinetic contribution of each effect not separated"]},{"year":2019,"claim":"Extended the function to archaea and tied the modification to physiology, showing Trm11 produces m2G10/m2,2G10 and supports tRNA stability at high temperature.","evidence":"Gene deletion in T. kodakarensis, LC-MS modification analysis, and high-temperature growth assays","pmids":["31405913"],"confidence":"Medium","gaps":["Mechanism of thermal stabilization not established","Relevance to mesophilic eukaryotic tRNA unclear"]},{"year":2020,"claim":"Provided direct structural basis for Trm112-dependent activation through crystal structures of the archaeal Trm11-Trm112 complex and inhibitor-bound Trm11.","evidence":"X-ray crystallography of multiple forms plus comparative in vitro activity assays of Trm11 alone versus complex","pmids":["33035335"],"confidence":"High","gaps":["Human Trm11-Trm112 structure not solved","Conformational changes during catalysis not captured"]},{"year":2022,"claim":"Mapped the tRNA substrate determinants required for methylation, defining positive and negative recognition elements.","evidence":"In vitro methyltransferase assays with 60 tRNA transcript variants plus tRNA purified from wild-type and trm11 deletion yeast","pmids":["35409407"],"confidence":"High","gaps":["Structural basis of negative determinant exclusion not resolved","How determinants generalize across all cellular tRNAs untested"]},{"year":2023,"claim":"Confirmed the human enzyme's activity and assigned a cellular function, showing TRMT11 methylates tRNA position 10 and that its loss with THUMPD3 impairs translation and proliferation.","evidence":"Co-IP of TRMT112 interactome in human cells, LC-MS/MS tRNA modification analysis, and siRNA knockdown with translation and proliferation assays","pmids":["37283053"],"confidence":"High","gaps":["Single-knockdown phenotype of TRMT11 alone modest","Direct mechanistic link between m2G10 and translational fidelity not defined"]},{"year":2023,"claim":"Identified an unexpected mRNA substrate, showing yeast Trm11 can m2G-modify mRNA codons and that this impedes ribosomal amino acid addition.","evidence":"LC-MS/MS mRNA modification profiling and reconstituted in vitro translation with modified mRNA","pmids":["37181630"],"confidence":"Medium","gaps":["mRNA methylation is a novel finding from a single study","In vivo prevalence and regulatory role of mRNA m2G unknown"]},{"year":null,"claim":"How m2G10 deposition is regulated in cells and how its loss propagates to translational and proliferative phenotypes in humans remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No human TRMT11-TRMT112 structure","Physiological role of mRNA methylation undefined","Disease association not established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,7,10]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,9,10]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9,10]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,10]}],"complexes":["Trm11-Trm112 tRNA methyltransferase complex"],"partners":["TRMT112","THUMPD3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z4G4","full_name":"tRNA (guanine(10)-N(2))-methyltransferase TRMT11","aliases":["tRNA methyltransferase 11 homolog"],"length_aa":463,"mass_kda":53.4,"function":"Catalytic subunit of the TRMT11-TRM112 methyltransferase complex, that specifically mediates the S-adenosyl-L-methionine-dependent N(2)-methylation of guanosine nucleotide at position 10 (m2G10) in tRNAs (PubMed:37283053). This is one of the major tRNA (guanine-N(2))-methyltransferases (PubMed:37283053)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q7Z4G4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRMT11","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRMT11","total_profiled":1310},"omim":[{"mim_id":"621532","title":"THUMP DOMAIN PROTEIN 3, tRNA GUANOSINE METHYLTRANSFERASE; THUMPD3","url":"https://www.omim.org/entry/621532"},{"mim_id":"621531","title":"tRNA METHYLTRANSFERASE 11; TRMT11","url":"https://www.omim.org/entry/621531"},{"mim_id":"618630","title":"tRNA METHYLTRANSFERASE SUBUNIT 11-2; TRMT112","url":"https://www.omim.org/entry/618630"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear bodies","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRMT11"},"hgnc":{"alias_symbol":["MDS024","dJ187J11.2","TRM11","TRMT11-1"],"prev_symbol":["C6orf75"]},"alphafold":{"accession":"Q7Z4G4","domains":[{"cath_id":"3.30.2130.30","chopping":"7-178","consensus_level":"high","plddt":91.7844,"start":7,"end":178},{"cath_id":"3.40.50.150","chopping":"181-315_344-440","consensus_level":"high","plddt":91.6625,"start":181,"end":440}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z4G4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z4G4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z4G4-F1-predicted_aligned_error_v6.png","plddt_mean":88.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRMT11","jax_strain_url":"https://www.jax.org/strain/search?query=TRMT11"},"sequence":{"accession":"Q7Z4G4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z4G4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z4G4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z4G4"}},"corpus_meta":[{"pmid":"15899842","id":"PMC_15899842","title":"Trm11p and Trm112p are both required for the formation of 2-methylguanosine at position 10 in yeast tRNA.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15899842","citation_count":101,"is_preprint":false},{"pmid":"25625329","id":"PMC_25625329","title":"Two-subunit enzymes involved in eukaryotic post-transcriptional tRNA modification.","date":"2014","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/25625329","citation_count":92,"is_preprint":false},{"pmid":"21478168","id":"PMC_21478168","title":"Mechanism of activation of methyltransferases involved in translation by the Trm112 'hub' protein.","date":"2011","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/21478168","citation_count":67,"is_preprint":false},{"pmid":"30705370","id":"PMC_30705370","title":"Identification of recurrent fusion genes across multiple cancer types.","date":"2019","source":"Scientific 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standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"Yeast Trm11p (ortholog of human TRMT11) is the catalytic subunit of the tRNA m2G10 methyltransferase, which requires Trm112p as an obligate partner subunit; together they catalyze formation of N2-methylguanosine at position 10 in tRNA, using S-adenosylmethionine as methyl donor.\",\n      \"method\": \"Genetic deletion, in vivo co-immunoprecipitation, in vitro methyltransferase assay with purified complex\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — enzymatic activity demonstrated in vitro, catalytic subunit assignment confirmed by deletion mutants and co-IP, replicated across multiple subsequent studies\",\n      \"pmids\": [\"15899842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRM11 genetically interacts with TRM1 (the m2,2G26 methyltransferase), suggesting that absence of m2G10 and m2,2G26 together affects tRNA metabolism or function.\",\n      \"method\": \"Genetic epistasis / double-deletion analysis in yeast\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic interaction observed in single study, no molecular mechanism elucidated beyond the phenotypic observation\",\n      \"pmids\": [\"15899842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Active yeast Trm11-Trm112 complex was reconstituted in a wheat germ cell-free translation system, confirming that co-expression of both subunits is sufficient to reconstitute m2G10 methyltransferase activity.\",\n      \"method\": \"Cell-free reconstitution (wheat germ cell-free translation) followed by methyltransferase activity assay\",\n      \"journal\": \"Nucleic acids symposium series\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution of activity, but single study with limited methodological detail in abstract\",\n      \"pmids\": [\"19749381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Trm112 activates Trm11 (as well as Trm9 and Mtq2) through a common structural mechanism: the Mtq2-Trm112 crystal structure, validated by site-directed mutagenesis and in vivo functional experiments, serves as a model for all three Trm112-methyltransferase complexes including Trm11-Trm112.\",\n      \"method\": \"X-ray crystallography of Mtq2-Trm112 complex, site-directed mutagenesis, in vivo functional assays, structural modeling of Trm11-Trm112\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis plus in vivo functional validation in one study; Trm11-Trm112 inferred by structural modeling with experimental support\",\n      \"pmids\": [\"21478168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of multiple Trm112-methyltransferase complexes reveal structural plasticity: Trm112 uses a similar interaction surface to activate Trm9, Trm11, Bud23, and Mtq2 despite those partners sharing less than 20% sequence identity.\",\n      \"method\": \"X-ray crystallography of Trm9-Trm112 complex; comparative structural analysis of known Trm112-MTase crystal structures\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with structure-function analysis; Trm11-Trm112 interaction mode inferred from comparative structural data with strong supporting evidence across multiple complexes\",\n      \"pmids\": [\"26438534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Trm112 activates Trm11 enzymatic activity by influencing S-adenosyl-L-methionine (SAM) binding and by contributing to tRNA substrate binding; hydrogen-deuterium exchange mass spectrometry showed the Trm11-Trm112 interaction relies on the same molecular interface as other Trm112-methyltransferase complexes, meaning all Trm112-dependent methyltransferases compete for the same binding surface on Trm112.\",\n      \"method\": \"Enzymatic activity assays (in vitro methyltransferase), hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS)\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay plus orthogonal HDX-MS structural probing, mechanistic dissection of SAM-binding and tRNA-binding contributions, single lab but two orthogonal methods\",\n      \"pmids\": [\"27986851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Archaeal Trm11 (ortholog) from Thermococcus kodakarensis is required for formation of m2G10 and m2,2G10 in tRNA; deletion of trm11 results in poor growth at 95°C, indicating the m2,2G10 modification contributes to tRNA stabilization at high temperatures.\",\n      \"method\": \"Gene deletion in T. kodakarensis, LC-MS tRNA modification analysis, growth phenotype assay at high temperature\",\n      \"journal\": \"Journal of bacteriology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean gene deletion with defined molecular (LC-MS modification loss) and physiological phenotype, single lab\",\n      \"pmids\": [\"31405913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structures of the Archaeoglobus fulgidus Trm11-Trm112 complex and of Trm11 alone (or bound to sinefungin inhibitor) reveal the molecular basis of Trm112-dependent activation: AfTrm11 is active as a single protein but its enzymatic activity is strongly enhanced by AfTrm112, and the interaction resembles eukaryotic Trm11-Trm112 complexes.\",\n      \"method\": \"X-ray crystallography, in vitro methyltransferase activity assays comparing Trm11 alone vs. Trm11-Trm112 complex\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures (multiple forms) plus quantitative in vitro activity assays, mechanistic conclusion well supported by two orthogonal methods in single rigorous study\",\n      \"pmids\": [\"33035335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human TRMT112 (the activator hub) interacts with TRMT11 along with six other methyltransferases; TRMT112 stabilizes all partner MTases including TRMT11 in cells, and single amino acid mutations on the TRMT112 surface reveal differential binding contributions across partners.\",\n      \"method\": \"SILAC co-immunoprecipitation screen (pulldown of TRMT112), western blot stability assays, site-directed mutagenesis of TRMT112\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — quantitative proteomics pulldown (SILAC) plus mutagenesis and stability assays, single lab, interaction and stabilization function established for TRMT11 specifically\",\n      \"pmids\": [\"34948388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The eukaryotic Trm11-Trm112 complex requires specific tRNA structural elements for methylation: mature tRNA (not precursor) with CCA terminus, a regular-size variable region, G10-C25 base pair, and anticodon-loop contacts are needed; U38 in tRNAAla and U32-A38 base pair in tRNACys act as negative determinants.\",\n      \"method\": \"In vitro methyltransferase assays with 60 tRNA transcript variants; purification of tRNAValAAC1 from wild-type and trm11 deletion yeast strains\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic in vitro substrate specificity mapping with 60 variants plus in vivo confirmation using deletion strains, comprehensive mechanistic substrate mapping\",\n      \"pmids\": [\"35409407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human TRMT11, identified as a direct partner of TRMT112 in intact human cells, is an active N2-methylguanosine (m2G) methyltransferase that methylates position 10 of tRNAs; combined loss of TRMT11 and THUMPD3 impairs optimal protein synthesis and cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation of TRMT112 interactome in human cells, LC-MS/MS tRNA modification analysis, siRNA knockdown with translation and proliferation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — enzymatic activity demonstrated biochemically in human cells, substrate (tRNA position 10) confirmed by mass spectrometry, functional consequence of loss shown by two orthogonal cellular assays\",\n      \"pmids\": [\"37283053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Yeast Trm11 incorporates N2-methylguanosine (m2G) into mRNA codons in addition to tRNA; m2G introduced into mRNA codons impedes amino acid addition by the ribosome in a position-dependent manner, as shown in a reconstituted translation system.\",\n      \"method\": \"LC-MS/MS mRNA modification profiling, mRNA purification, reconstituted in vitro translation assay with modified mRNA substrates\",\n      \"journal\": \"RSC chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution of translation inhibition and LC-MS/MS modification detection, but mRNA methylation by Trm11 is a novel and unexpected finding from a single study\",\n      \"pmids\": [\"37181630\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRMT11 (yeast Trm11) is the catalytic subunit of a two-subunit tRNA methyltransferase that, together with its obligate activator partner TRMT112, catalyzes S-adenosylmethionine-dependent N2-methylation of guanosine at position 10 in tRNA; TRMT112 enhances enzymatic activity by promoting SAM binding and tRNA substrate engagement through a conserved protein–protein interface, and mature tRNA with a CCA terminus, G10-C25 base pair, and appropriate anticodon-loop contacts are required as substrate determinants.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRMT11 (yeast Trm11) is the catalytic subunit of a tRNA methyltransferase that installs N2-methylguanosine at position 10 (m2G10) using S-adenosylmethionine as methyl donor, a reaction strictly dependent on the obligate partner subunit TRMT112 [#0]. TRMT112 activates TRMT11 through a conserved protein–protein interface shared across the Trm112-dependent methyltransferase family, enhancing catalysis by promoting SAM binding and contributing to tRNA substrate engagement; this same surface is used competitively by all of TRMT112's methyltransferase partners [#5, #7]. In human cells TRMT11 is a direct TRMT112 interactor and an active m2G methyltransferase acting on tRNA position 10, and TRMT112 stabilizes TRMT11 protein in cells [#8, #10]. Substrate recognition requires mature tRNA bearing a CCA terminus, a G10-C25 base pair, a regular variable region, and appropriate anticodon-loop contacts, with specific anticodon-loop features acting as negative determinants [#9]. Functionally, combined loss of TRMT11 and THUMPD3 impairs optimal protein synthesis and cell proliferation, linking the modification to translational fidelity [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the enzymatic identity of TRMT11 by showing the yeast ortholog is the catalytic subunit of the m2G10 tRNA methyltransferase, requiring Trm112 as an obligate partner.\",\n      \"evidence\": \"Genetic deletion, in vivo co-IP, and in vitro methyltransferase assay with purified complex in yeast\",\n      \"pmids\": [\"15899842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the Trm11-Trm112 interaction not defined\", \"Substrate determinants on tRNA not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linked m2G10 to broader tRNA modification networks via genetic interaction between TRM11 and the m2,2G26 methyltransferase TRM1.\",\n      \"evidence\": \"Genetic epistasis / double-deletion analysis in yeast\",\n      \"pmids\": [\"15899842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for the interaction beyond phenotype\", \"Functional consequence of combined modification loss unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Confirmed that co-expression of both subunits is sufficient to reconstitute active enzyme, supporting the two-subunit model.\",\n      \"evidence\": \"Wheat germ cell-free reconstitution followed by methyltransferase activity assay\",\n      \"pmids\": [\"19749381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited methodological detail\", \"Quantitative kinetics not reported\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined Trm112 as a common structural activator across multiple methyltransferases, providing a structural model for Trm11-Trm112 activation.\",\n      \"evidence\": \"X-ray crystallography of Mtq2-Trm112, site-directed mutagenesis, in vivo functional assays, and structural modeling\",\n      \"pmids\": [\"21478168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trm11-Trm112 interface inferred by modeling rather than direct structure\", \"Catalytic mechanism not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that Trm112 uses one conserved surface to activate diverse partners despite low sequence identity, framing Trm11 as one of several competing clients.\",\n      \"evidence\": \"X-ray crystallography of Trm9-Trm112 and comparative structural analysis of Trm112-MTase complexes\",\n      \"pmids\": [\"26438534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Trm11-Trm112 structure still not solved at this point\", \"Competition dynamics in vivo unquantified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Dissected the activation mechanism, showing Trm112 enhances Trm11 activity via effects on SAM binding and tRNA engagement through a shared interface used by all partners.\",\n      \"evidence\": \"In vitro methyltransferase assays plus hydrogen-deuterium exchange mass spectrometry\",\n      \"pmids\": [\"27986851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution Trm11-Trm112 structure not yet available\", \"Kinetic contribution of each effect not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the function to archaea and tied the modification to physiology, showing Trm11 produces m2G10/m2,2G10 and supports tRNA stability at high temperature.\",\n      \"evidence\": \"Gene deletion in T. kodakarensis, LC-MS modification analysis, and high-temperature growth assays\",\n      \"pmids\": [\"31405913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of thermal stabilization not established\", \"Relevance to mesophilic eukaryotic tRNA unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided direct structural basis for Trm112-dependent activation through crystal structures of the archaeal Trm11-Trm112 complex and inhibitor-bound Trm11.\",\n      \"evidence\": \"X-ray crystallography of multiple forms plus comparative in vitro activity assays of Trm11 alone versus complex\",\n      \"pmids\": [\"33035335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human Trm11-Trm112 structure not solved\", \"Conformational changes during catalysis not captured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped the tRNA substrate determinants required for methylation, defining positive and negative recognition elements.\",\n      \"evidence\": \"In vitro methyltransferase assays with 60 tRNA transcript variants plus tRNA purified from wild-type and trm11 deletion yeast\",\n      \"pmids\": [\"35409407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of negative determinant exclusion not resolved\", \"How determinants generalize across all cellular tRNAs untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed the human enzyme's activity and assigned a cellular function, showing TRMT11 methylates tRNA position 10 and that its loss with THUMPD3 impairs translation and proliferation.\",\n      \"evidence\": \"Co-IP of TRMT112 interactome in human cells, LC-MS/MS tRNA modification analysis, and siRNA knockdown with translation and proliferation assays\",\n      \"pmids\": [\"37283053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-knockdown phenotype of TRMT11 alone modest\", \"Direct mechanistic link between m2G10 and translational fidelity not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an unexpected mRNA substrate, showing yeast Trm11 can m2G-modify mRNA codons and that this impedes ribosomal amino acid addition.\",\n      \"evidence\": \"LC-MS/MS mRNA modification profiling and reconstituted in vitro translation with modified mRNA\",\n      \"pmids\": [\"37181630\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mRNA methylation is a novel finding from a single study\", \"In vivo prevalence and regulatory role of mRNA m2G unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How m2G10 deposition is regulated in cells and how its loss propagates to translational and proliferative phenotypes in humans remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No human TRMT11-TRMT112 structure\", \"Physiological role of mRNA methylation undefined\", \"Disease association not established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 7, 10]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 9, 10]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9, 10]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"complexes\": [\"Trm11-Trm112 tRNA methyltransferase complex\"],\n    \"partners\": [\"TRMT112\", \"THUMPD3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}