Affinage

TRMT112

Multifunctional methyltransferase subunit TRM112-like protein · UniProt Q9UI30

Length
125 aa
Mass
14.2 kDa
Annotated
2026-04-28
30 papers in source corpus 20 papers cited in narrative 20 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRMT112 is an evolutionarily conserved obligate co-factor that activates at least seven methyltransferases—METTL5, WBSCR22/BUD23, N6AMT1/HEMK2, TRMT11, THUMPD3, THUMPD2, and ALKBH8—by forming stable heterodimeric complexes through a conserved β-zipper/hydrophobic interface, thereby coordinating methylation of rRNA, tRNA, and translation termination factors (PMID:21478168, PMID:26438534, PMID:34948388). TRMT112 stabilizes each partner against ubiquitin–proteasome-dependent degradation, and in several complexes it directly contributes to SAM cofactor or RNA substrate binding; different methyltransferase partners compete for a shared interaction surface on TRMT112 (PMID:27986851, PMID:26214185, PMID:31328227). Through these partnerships, TRMT112 controls 18S rRNA m6A (via METTL5) and m7G (via WBSCR22) modifications required for ribosome biogenesis, tRNA m2G modifications at positions 6/7 (via THUMPD3) and 10 (via TRMT11) that promote translational fidelity and efficiency, and glutamine methylation of eRF1 (via N6AMT1) needed for translation termination (PMID:35033535, PMID:34669960, PMID:31636962, PMID:25489090). Loss of THUMPD3–TRMT112-dependent tRNA modification suppresses TFEB translation and autophagic flux, linking TRMT112's methyltransferase-activating function to downstream cellular programs including autophagy and cell growth (PMID:41530782).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 High

    Determining how TRMT112 activates structurally diverse methyltransferases, the crystal structure of yeast Mtq2–Trm112 established that TRMT112 uses a single conserved binding mode to activate partners with less than 20% sequence identity, directly enabling Gln methylation of translation termination factor eRF1.

    Evidence Crystal structure of Mtq2–Trm112 with site-directed mutagenesis and in vivo functional assays in yeast

    PMID:21478168

    Open questions at the time
    • No structural basis for how TRMT112 discriminates among multiple partners
    • Mammalian Mtq2/N6AMT1 complex not yet structurally resolved at this point
  2. 2012 High

    Establishing TRMT112 as essential for ribosome biogenesis, loss of Trm112 in yeast abolished Bud23-mediated 18S rRNA m7G1575 modification, destabilized Bud23 protein, prevented its recruitment to pre-ribosomes, and triggered nucleolar surveillance-mediated preribosome degradation, revealing TRMT112 as a stabilizer and recruitment factor for its partners.

    Evidence In vitro binding, in vivo stability assays, co-purification with pre-rRNAs, and methylation assays in S. cerevisiae deletion strains

    PMID:22493060 PMID:22956767

    Open questions at the time
    • Whether TRMT112 has partners outside the methyltransferase family
    • How TRMT112 partitions among competing partners in vivo
  3. 2014 High

    Resolving the atomic architecture of the rRNA methyltransferase complex, crystal structures of Bud23–Trm112 in apo and SAM-bound states revealed the β-zipper interface mechanism and showed Trm112 undergoes induced fit upon partner binding, explaining its structural plasticity.

    Evidence Crystal structures (apo and SAM-bound), mutagenesis, sucrose gradient sedimentation, and co-IP in yeast

    PMID:25489090

    Open questions at the time
    • Whether the induced-fit mechanism generalizes to all TRMT112 partners
    • No structure of TRMT112 bound to an RNA substrate
  4. 2015 High

    Extending the mechanism to human cells, TRMT112 was shown to determine the nuclear localization and protein stability of WBSCR22, which is ubiquitinated and degraded by the proteasome when not stabilized by TRMT112; ribosome biogenesis required WBSCR22 presence rather than catalytic activity, indicating a quality-control checkpoint function.

    Evidence SILAC-Co-IP, siRNA knockdown, subcellular fractionation, ubiquitination assays, and catalytic-dead mutant analysis in human cells; crystal structure of yeast Trm9–Trm112

    PMID:25851604 PMID:26214185 PMID:26438534

    Open questions at the time
    • How TRMT112 shields partners from ubiquitin ligases
    • Identity of the E3 ligase targeting free methyltransferase partners
  5. 2017 High

    Addressing how TRMT112 activates tRNA methyltransferases, HDX-MS and enzymatic assays showed that Trm112 enhances SAM cofactor binding and contributes to tRNA recognition in the Trm11–Trm112 complex, and that all Trm112-dependent methyltransferases compete for the same molecular interface.

    Evidence HDX-MS, SAM-binding assays, and enzymatic activity measurements with purified yeast complexes

    PMID:27986851

    Open questions at the time
    • In vivo stoichiometry and kinetic hierarchy of partner competition
    • Whether post-translational modifications regulate partner preference
  6. 2019 High

    Identifying TRMT112 as essential for 18S rRNA m6A modification, the METTL5–TRMT112 crystal structure revealed an RNA-binding mode distinct from other m6A writers with an adenosine extrusion mechanism; separately, the human N6AMT1–TRMT112 structure confirmed the complex is a protein glutamine methyltransferase (not a DNA methyltransferase).

    Evidence Crystal structures, co-IP, rRNA modification mapping, in vitro methyltransferase assays, and protein stability assays in human cells

    PMID:31328227 PMID:31636962

    Open questions at the time
    • No RNA-bound co-crystal structure of METTL5–TRMT112
    • How the complex is recruited to 18S rRNA in vivo
  7. 2021 High

    Defining the full human TRMT112 interactome, SILAC proteomics identified seven methyltransferase partners (N6AMT1, WBSCR22, METTL5, ALKBH8, THUMPD2, THUMPD3, TRMT11), all stabilized by TRMT112 with a mutual feedback loop; THUMPD3–TRMT112 was shown to be an active tRNA m2G6/7 methyltransferase whose loss impairs global protein synthesis.

    Evidence SILAC-Co-IP, mutagenesis, co-expression stability assays, RNA-MS, in vitro enzymatic assays, knockout cell analysis

    PMID:34669960 PMID:34948388

    Open questions at the time
    • Whether additional partners exist beyond the seven identified
    • Structural basis of THUMPD3–TRMT112 substrate recognition
  8. 2022 High

    Refining substrate specificity rules, the Trm11–Trm112 complex was shown to require mature tRNA features (CCA terminus, G10–C25 base pair, regular variable region) for m2G10 modification, excluding pre-tRNAs as substrates; METTL5 mutations causing microcephaly/intellectual disability were found to disrupt the METTL5–TRMT112 interaction.

    Evidence Systematic in vitro methylation with 60 tRNA variants in yeast; METTL5 disease-mutation analysis with co-IP and rRNA modification mapping in human cells and mouse models

    PMID:35033535 PMID:35409407

    Open questions at the time
    • Whether TRMT112 dysfunction alone causes human disease
    • Tissue-specific consequences of individual partner loss
  9. 2026 High

    Demonstrating partner-specific druggability, covalent stereoprobes were found to react selectively with TRMT112 C100 only when complexed with METTL5, exploiting a composite pocket absent in other TRMT112 complexes; separately, THUMPD3–TRMT112 was linked to TFEB translational control and autophagy regulation in pancreatic cancer.

    Evidence Chemical proteomics with co-crystal structure of stereoprobe-bound METTL5–TRMT112; knockdown, polysome profiling, xenograft models for THUMPD3–TRMT112 in pancreatic cancer

    PMID:41507545 PMID:41530782

    Open questions at the time
    • Whether allosteric agonism of METTL5 by stereoprobes alters cellular rRNA methylation
    • Broader translational targets beyond TFEB controlled by THUMPD3–TRMT112

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how TRMT112 is partitioned among its seven competing partners in vivo, whether TRMT112 loss-of-function mutations directly cause human Mendelian disease, and the structural basis for TRMT112 complexes with THUMPD2, THUMPD3, and ALKBH8.
  • No in vivo quantitative model of partner competition and stoichiometry
  • No human disease mutations mapped to TRMT112 itself
  • No crystal structures of TRMT112 with THUMPD2, THUMPD3, or ALKBH8

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 3 GO:0098772 molecular function regulator activity 3 GO:0003723 RNA binding 2
Localization
GO:0005730 nucleolus 2 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-9612973 Autophagy 1
Partners
ALKBH8METTL5N6AMT1THUMPD2THUMPD3TRMT11WBSCR22
Complex memberships
METTL5-TRMT112N6AMT1/HEMK2-TRMT112THUMPD3-TRMT112WBSCR22/BUD23-TRMT112

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 METTL5 must form a heterodimeric complex with TRMT112 to gain metabolic stability in cells; the METTL5-TRMT112 complex is responsible for N6-methyladenosine (m6A) modification of 18S rRNA, and the first atomic resolution structure of METTL5-TRMT112 was determined, revealing an RNA-binding mode distinct from other m6A methyltransferases and suggesting an adenosine extrusion mechanism. Co-immunoprecipitation, crystal structure determination, in vivo stability assays, rRNA modification mapping Nucleic acids research High 31328227
2015 Human WBSCR22 (Bud23 ortholog) forms a complex with TRMT112 to methylate G in 18S rRNA and is required for pre-rRNA processing leading to 18S rRNA synthesis; importantly, ribosome biogenesis requires the presence of the methyltransferase rather than its catalytic activity, indicating a quality control role for TRMT112-dependent methyltransferase binding to nascent pre-rRNAs. Functional complementation assays, pre-rRNA processing analysis, catalytic mutant studies in human cells Molecular biology of the cell High 25851604
2014 Bud23-Trm112 (yeast ortholog complex) catalyzes N7-methylguanosine at position G1575 of 18S rRNA; crystal structures of apo and SAM-bound forms show Bud23 and Trm112 interact via a β-zipper involving main-chain atoms, burying a hydrophobic surface; Trm112 undergoes induced fit to accommodate Bud23; m7G methylation occurs at a late step of small subunit biogenesis despite early recruitment; Bud23-Trm112 interacts directly with the DEAH helicase Dhr1. Crystal structure determination (apo and SAM-bound), site-directed mutagenesis, co-immunoprecipitation, sucrose gradient sedimentation, in vivo methylation assays Proceedings of the National Academy of Sciences of the United States of America High 25489090
2012 In S. cerevisiae, Trm112 is required for efficient ribosome synthesis and mitosis progression; Trm112 interacts directly with Bud23 in vitro and is required for Bud23 stability in vivo; without Trm112, Bud23-mediated 18S rRNA methylation at G1575 is lost, Bud23 fails to bind nascent preribosomes, and a nucleolar surveillance pathway involving TRAMP complexes degrades preribosomes. In vitro binding assay, co-purification with pre-rRNAs, in vivo stability assays, methylation assays, genetic deletion analysis Molecular and cellular biology High 22493060
2011 The Mtq2-Trm112 holoenzyme methylates the glutamine of the GGQ motif in eukaryotic translation termination factor eRF1; crystal structure of Mtq2-Trm112 complex was determined and active site mapped; Trm112 uses a common structural strategy to activate Mtq2, Trm9, and Trm11 methyltransferases despite their low sequence identity (<20%). Crystal structure determination, site-directed mutagenesis, in vivo functional experiments Nucleic acids research High 21478168
2012 Trm112 is required for both small (40S) and large (60S) ribosomal subunit biogenesis in yeast; Trm112 stabilizes free methyltransferase partners not engaged with substrate; Trm112 also interacts with Nop2 and Rcm1, which are linked to 60S biogenesis. Sucrose gradient sedimentation, co-immunoprecipitation, genetic suppression analysis Molecular biology of the cell High 22956767
2015 TRMT112 is the interaction partner of WBSCR22 in human cells; knockdown of TRMT112 decreases WBSCR22 protein levels; TRMT112 determines the nuclear localization of WBSCR22; WBSCR22 is ubiquitinated and degraded via the proteasome pathway when not stabilized by TRMT112. SILAC-coupled co-immunoprecipitation, siRNA knockdown, subcellular fractionation/localization imaging, ubiquitination assay, proteasome inhibitor treatment PloS one High 26214185
2017 Trm112 activates the Trm11-Trm112 complex by influencing S-adenosyl-L-methionine (SAM) binding and contributing to tRNA binding; all Trm112-dependent methyltransferases compete to interact with Trm112 through similar molecular interfaces. Enzymatic activity assays, hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS), SAM-binding experiments Nucleic acids research High 27986851
2015 Crystal structure of Trm9-Trm112 complex reveals structural plasticity allowing Trm112 to interact similarly with multiple methyltransferase partners despite low sequence identity; Trm9-Trm112 modifies the tRNA anticodon wobble position (mcm5U modification) to promote translational fidelity. Crystal structure determination, structure-function analysis Nucleic acids research High 26438534
2021 THUMPD3 interacts with TRMT112 to form an active tRNA m2G methyltransferase; THUMPD3 alone cannot modify tRNAs but THUMPD3-TRMT112 together methylate the 2-amino group of G at position 6 (and G7 in tRNATrp) of 26 tested G6-containing human cytoplasmic tRNAs, recognizing the 3'-CCA terminus of mature tRNAs; THUMPD3 knockout impairs global protein synthesis and reduces cell growth. Reverse genetics, RNA-mass spectrometry, in vitro enzymatic assay, co-immunoprecipitation, knockout cell line analysis Nucleic acids research High 34669960
2019 Crystal structure of human N6AMT1 (HEMK2)-TRMT112 complex bound to SAM shows Trm112 binds a hydrophobic surface of N6AMT1 to stabilize its structure without directly contributing to substrate binding or catalysis; biochemical data confirm the complex has no DNA methyltransferase activity but methylates Gln185 of eRF1, establishing N6AMT1 as a protein glutamine methyltransferase. Crystal structure determination, DNA binding assays, in vitro methyltransferase activity assays Cell discovery High 31636962
2020 Crystal structure of HEMK2 (N6AMT1)-TRMT112 complexes (SAM-bound and post-catalytic SAH/methylglutamine-bound) reveals a specific pocket in HEMK2 for accommodating glutamine substrate and catalyzing methylation; HEMK2 can methylate both lysine and glutamine residues. Crystal structure determination, mass spectrometry, in vitro methylation assays The Biochemical journal High 32969463
2018 In archaea (Haloferax volcanii), Trm112 orthologs interact with and activate multiple methyltransferases targeting translation machinery components, extending the Trm112 methyltransferase activation network beyond eukaryotes to include archaeal partners, some orthologous to eukaryotic partners and others similar to bacterial methyltransferases. Functional and structural characterization, interaction network mapping, native mass spectrometry Nucleic acids research Medium 30010922
2021 Human TRMT112 interacts with seven methyltransferases (N6AMT1, WBSCR22, METTL5, ALKBH8, THUMPD2, THUMPD3, TRMT11) identified by SILAC screen; TRMT112 stabilizes all seven MTases in cells; a strong mutual feedback loop exists between TRMT112 and its MTase partners; single amino acid mutations on TRMT112 surface reveal differential interaction requirements. SILAC co-immunoprecipitation, co-expression stability assays, site-directed mutagenesis International journal of molecular sciences High 34948388
2022 The METTL5-TRMT112 complex installs the m6A modification at position 1832 of human 18S rRNA; TRMT112 is required for METTL5 stability; METTL5 mutations associated with microcephaly/intellectual disability disrupt the METTL5-TRMT112 interaction; loss of METTL5 regulates gene expression at the translational level. Methyltransferase activity assays, co-immunoprecipitation, rRNA modification mapping, polysome profiling, mouse knockout studies The Journal of biological chemistry High 35033535
2021 BUD23-TRMT112 complex mediates chromosomal tethering of Borna disease virus 1 (BoDV-1) viral ribonucleoproteins (vRNPs); TRMT112 binds BoDV-1 L protein at the RNA-dependent RNA polymerase domain together with BUD23; the MTase activity of BUD23-TRMT112 is necessary for this chromosomal tethering. Proximity-dependent biotinylation, co-immunoprecipitation, chromosomal tethering assays, catalytic mutant analysis Microbiology and immunology Medium 34324219
2019 TRMT112 regulates the expression of N6AMT1 isoforms: only isoform 1 (with intact substrate binding motif) can interact with TRMT112; the alternatively spliced isoform 2 (lacking substrate binding motif) cannot interact with TRMT112 and is rapidly degraded, establishing TRMT112 as part of a cellular quality control mechanism. Co-immunoprecipitation, protein stability assays, siRNA knockdown, isoform expression analysis Biomolecules Medium 31466382
2026 Covalent stereoprobes react selectively with C100 of TRMT112 only when TRMT112 is complexed with METTL5 (not other MT partners); a co-crystal structure reveals stereoprobe binding to a composite pocket templated by METTL5 and absent in other TRMT112:MT complexes; stereoprobe binding causes allosteric agonism of METTL5, demonstrating that TRMT112's C100 is part of a partner-specific composite binding site. Chemical proteomics, co-crystal structure determination, covalent probe reactivity assays Nature chemical biology High 41507545
2022 In yeast, the Trm11-Trm112 complex requires the CCA terminus of mature tRNA, a G10-C25 base pair, a regular-size variable region, and specific anticodon loop features for m2G10 methylation; precursor tRNA is not a substrate. In vitro methylation assays with 60 tRNA transcript variants, purification of tRNA from wild-type and deletion strains International journal of molecular sciences Medium 35409407
2026 THUMPD3-TRMT112 complex promotes TFEB translation via m2G modification of tRNALeu(CAG); deficiency of THUMPD3/TRMT112 suppresses TFEB translation, reduces autophagic flux, and inhibits pancreatic cancer cell growth. Knockdown experiments, polysome profiling, in vivo xenograft, autophagic flux assays, mechanistic tRNA modification analysis Molecular cancer Medium 41530782

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112. Nucleic acids research 416 31328227
2015 The human 18S rRNA base methyltransferases DIMT1L and WBSCR22-TRMT112 but not rRNA modification are required for ribosome biogenesis. Molecular biology of the cell 140 25851604
2014 Structural and functional studies of Bud23-Trm112 reveal 18S rRNA N7-G1575 methylation occurs on late 40S precursor ribosomes. Proceedings of the National Academy of Sciences of the United States of America 84 25489090
2012 Trm112 is required for Bud23-mediated methylation of the 18S rRNA at position G1575. Molecular and cellular biology 75 22493060
2011 Mechanism of activation of methyltransferases involved in translation by the Trm112 'hub' protein. Nucleic acids research 66 21478168
2022 The METTL5-TRMT112 N6-methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation. The Journal of biological chemistry 60 35033535
2021 THUMPD3-TRMT112 is a m2G methyltransferase working on a broad range of tRNA substrates. Nucleic acids research 49 34669960
2017 Trm112, a Protein Activator of Methyltransferases Modifying Actors of the Eukaryotic Translational Apparatus. Biomolecules 49 28134793
2019 Structural insight into human N6amt1-Trm112 complex functioning as a protein methyltransferase. Cell discovery 38 31636962
2018 Evolutionary insights into Trm112-methyltransferase holoenzymes involved in translation between archaea and eukaryotes. Nucleic acids research 36 30010922
2015 Insights into molecular plasticity in protein complexes from Trm9-Trm112 tRNA modifying enzyme crystal structure. Nucleic acids research 35 26438534
2009 The Arabidopsis SMO2, a homologue of yeast TRM112, modulates progression of cell division during organ growth. The Plant journal : for cell and molecular biology 32 19929876
2017 Activation mode of the eukaryotic m2G10 tRNA methyltransferase Trm11 by its partner protein Trm112. Nucleic acids research 31 27986851
2012 The methyltransferase adaptor protein Trm112 is involved in biogenesis of both ribosomal subunits. Molecular biology of the cell 31 22956767
2022 WBSCR22 and TRMT112 synergistically suppress cell proliferation, invasion and tumorigenesis in pancreatic cancer via transcriptional regulation of ISG15. International journal of oncology 30 35088887
2015 The Stability of Ribosome Biogenesis Factor WBSCR22 Is Regulated by Interaction with TRMT112 via Ubiquitin-Proteasome Pathway. PloS one 29 26214185
2021 Human TRMT112-Methyltransferase Network Consists of Seven Partners Interacting with a Common Co-Factor. International journal of molecular sciences 23 34948388
2019 The Common Partner of Several Methyltransferases TRMT112 Regulates the Expression of N6AMT1 Isoforms in Mammalian Cells. Biomolecules 14 31466382
2009 Production of yeast (m2G10) methyltransferase (Trm11 and Trm112 complex) in a wheat germ cell-free translation system. Nucleic acids symposium series (2004) 13 19749381
2022 Pan-Cancer Analysis Reveals the Relation between TRMT112 and Tumor Microenvironment. Journal of oncology 12 36081672
2021 BUD23-TRMT112 interacts with the L protein of Borna disease virus and mediates the chromosomal tethering of viral ribonucleoproteins. Microbiology and immunology 11 34324219
2020 Structural and functional insights into Archaeoglobus fulgidus m2G10 tRNA methyltransferase Trm11 and its Trm112 activator. Nucleic acids research 11 33035335
2020 Structural insight into HEMK2-TRMT112-mediated glutamine methylation. The Biochemical journal 8 32969463
2022 Required Elements in tRNA for Methylation by the Eukaryotic tRNA (Guanine-N2-) Methyltransferase (Trm11-Trm112 Complex). International journal of molecular sciences 7 35409407
2026 Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5. Nature chemical biology 2 41507545
2025 Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5. bioRxiv : the preprint server for biology 1 40475643
2025 Multiomic Landscape Uncovers TRMT112 as a Central Driver of HPV-Positive Head and Neck Squamous Cell Carcinoma. Human mutation 1 41235342
2026 TRMT112 drives a tumor growth and metastasis-promoting program in triple-negative breast cancer. Cell death and differentiation 0 41507361
2026 tRNA m2G methyltransferase complex THUMPD3-TRMT112 promotes pancreatic cancer progression and autophagy via modulating TFEB translation. Molecular cancer 0 41530782
2026 High expression of TRMT112 is associated with the development of oral squamous cell carcinoma. Journal of oral biology and craniofacial research 0 41551838