METTL13

METTL13 is a dual-domain protein methyltransferase that post-translationally modifies the translation elongation factor eEF1A to control global and codon-specific translation (PMID:30143613). Its N-terminal domain tri-methylates the eEF1A N-terminus while a second lysine methyltransferase domain dimethylates eEF1A at Lys55, and structural and ribosome-profiling analyses establish that these modifications reshape translation dynamics (PMID:30143613). eEF1A-K55 dimethylation increases the intrinsic GTPase activity of eEF1A and raises protein output, an activity co-opted by Ras-driven cancers to elevate translation and promote tumorigenesis in vivo (PMID:30612740); this eEF1A-targeting role and its tumor-promoting dependence on eEF1A methylation are conserved in the C. elegans ortholog (PMID:37347777). METTL13 catalytic output is itself regulated through a tripartite complex with the Nα-trimethyltransferases METTL11A and METTL11B, in which METTL13 directly inhibits METTL11A activity while METTL11A reciprocally promotes K55 methylation but represses Nα-methylation by METTL13 (PMID:36889590). Beyond eEF1A, METTL13 methylates c-Cbl to block c-Cbl-mediated ubiquitination and degradation of SERCA2a, thereby preserving Ca2+ transients and contractile function in cardiomyocytes (PMID:37450238). A dominant METTL13 substitution acts as the DFNM1 suppressor of GAB1-associated DFNB26 deafness, where METTL13 co-immunoprecipitates with GAB1 and SPRY2 and modifies MET/HGF signaling (PMID:29408807). Across multiple cancers METTL13 influences proliferation and translational output (PMID:30178547, PMID:41764490), but the molecular basis of several of these context-specific roles is not resolved in the available corpus.

1. 2018 High

   Establishing what METTL13 does molecularly: it is a bifunctional methyltransferase with two domains targeting distinct sites on eEF1A, linking the enzyme directly to translational control.

   Evidence Biochemical methyltransferase assays, structural analysis, and ribosome profiling in cells

   PMID:30143613

   Open questions at the time

   • Did not establish the functional consequence of each individual methyl mark for GTPase activity
   • Codon-specific translation effects not connected to downstream phenotypes
2. 2018 Medium

   Connecting METTL13 to human disease and to a non-eEF1A interaction context, showing it forms a complex with GAB1/SPRY2 and modifies MET/HGF signaling as a genetic suppressor of deafness.

   Evidence Co-immunoprecipitation, zebrafish morphant rescue with human METTL13 mRNA, and mouse co-localization in auditory neurons

   PMID:29408807

   Open questions at the time

   • Whether suppression depends on METTL13 catalytic activity not resolved
   • Direct substrate within the GAB1/SPRY2/MET axis not identified
3. 2018 Medium

   Linking METTL13 to a developmental phenotype: it facilitates INSL3 production required for transabdominal testis migration.

   Evidence siRNA knockdown in MA-10 Leydig cells and Mettl13+/- mouse cryptorchidism phenotyping

   PMID:30178547

   Open questions at the time

   • Molecular substrate connecting METTL13 to INSL3/AMPK/cilia not identified
   • Whether the effect requires methyltransferase activity unknown
4. 2019 High

   Defining the functional payoff of K55 dimethylation: it activates eEF1A GTPase activity and boosts translation, a mechanism Ras-driven tumors exploit.

   Evidence In vitro GTPase assays, cell-based protein synthesis assays, and mouse tumor and patient-derived xenograft models

   PMID:30612740

   Open questions at the time

   • How the N-terminal trimethylation contributes alongside K55me2 not fully separated
   • Mechanism coupling increased GTPase activity to oncogenic selectivity unresolved
5. 2023 High

   Showing METTL13 activity is itself regulated by a methyltransferase complex, with reciprocal modulation of Nα- versus K55 methylation by METTL11A/11B.

   Evidence Co-IP, mass spectrometry, and in vitro methylation assays with catalytic mutants

   PMID:36889590

   Open questions at the time

   • Structural basis of the tripartite complex not determined
   • Physiological conditions selecting between Nα- and K55 methylation outputs unknown
6. 2023 Medium

   Extending METTL13 substrate scope beyond eEF1A: methylation of c-Cbl stabilizes SERCA2a to maintain cardiomyocyte Ca2+ handling.

   Evidence AAV9 cardiomyocyte overexpression, siRNA knockdown, Ca2+ imaging, ubiquitination assays, and mouse MI model

   PMID:37450238

   Open questions at the time

   • c-Cbl methylation site not mapped
   • Whether c-Cbl is a direct METTL13 substrate not shown by reconstitution
7. 2023 High

   Demonstrating evolutionary conservation of the eEF1A-methylation and tumor-promoting functions in an invertebrate ortholog while showing dispensability for normal development.

   Evidence Methyltransferase assays, mass spectrometry, and C. elegans genetic knockout models

   PMID:37347777

   Open questions at the time

   • Conservation of the c-Cbl/SERCA2a and complex-regulation functions not tested
8. 2025 Medium

   Probing whether METTL13 can act as an m6A writer, proposing CD44 mRNA decay control driving stemness and drug resistance via a USP10-stabilized complex.

   Evidence RNA pull-down, MS, co-IP, RIP, MeRIP, SELECT, and xenograft/organoid models

   PMID:39806412

   Open questions at the time

   • m6A writer activity for METTL13 is novel and not independently replicated
   • Direct catalytic deposition of m6A not demonstrated in vitro
9. 2025 Low

   Developing a chemical tool: a bisubstrate probe occupying both SAM and peptide pockets that engages METTL13 in cells.

   Evidence Molecular docking, MD simulation, and cellular thermal shift assay

   PMID:41468753

   Open questions at the time

   • Primarily computational with no in vitro enzymatic inhibition data
   • No structural confirmation of the bivalent binding mode
10. 2026 Medium

    Showing METTL13 acts at the translational level in cancer, enhancing SAA1 protein production to alter lipid metabolism and stemness.

    Evidence Polyribosome-bound mRNA sequencing, metabolic assays, and in vivo mouse models

    PMID:41764490

    Open questions at the time

    • Whether SAA1 translational enhancement is mediated through eEF1A methylation not established
    • Direct molecular link from METTL13 to SAA1 mRNA not defined

• Whether METTL13's many context-specific roles (deafness modification, cardiac SERCA2a stabilization, m6A-dependent mRNA decay, codon-specific cancer translation) all derive from its eEF1A methyltransferase activity or reflect independent substrate/complex functions remains unresolved.
• No unifying biochemical test separating catalytic from scaffolding roles across tissues
• Substrate sites for non-eEF1A targets largely unmapped