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Throll, P.* ; G Dolce, L.* ; Rico-Lastres, P. ; Arnold, K. ; Tengo, L.* ; Basu, S.* ; Kaiser, S.* ; Schneider, R. ; Kowalinski, E.*

Structural basis of tRNA recognition by the m3C RNA methyltransferase METTL6 in complex with SerRS seryl-tRNA synthetase.

Nat. Struct. Mol. Biol., DOI: 10.1038/s41594-024-01341-3 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
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Methylation of cytosine 32 in the anticodon loop of tRNAs to 3-methylcytosine (m3C) is crucial for cellular translation fidelity. Misregulation of the RNA methyltransferases setting this modification can cause aggressive cancers and metabolic disturbances. Here, we report the cryo-electron microscopy structure of the human m3C tRNA methyltransferase METTL6 in complex with seryl-tRNA synthetase (SerRS) and their common substrate tRNASer. Through the complex structure, we identify the tRNA-binding domain of METTL6. We show that SerRS acts as the tRNASer substrate selection factor for METTL6. We demonstrate that SerRS augments the methylation activity of METTL6 and that direct contacts between METTL6 and SerRS are necessary for efficient tRNASer methylation. Finally, on the basis of the structure of METTL6 in complex with SerRS and tRNASer, we postulate a universal tRNA-binding mode for m3C RNA methyltransferases, including METTL2 and METTL8, suggesting that these mammalian paralogs use similar ways to engage their respective tRNA substrates and cofactors.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords N-terminal Methyltransferase; Binding Protein Abp140; Crystal-structure; 3-methylcytidine Modification; Modified Nucleosides; Molecular-basis; Mechanism; Selection; Reveals; Domain
ISSN (print) / ISBN 1545-9993
e-ISSN 1545-9985
Journal Nature Structural & Molecular Biology
Publisher Nature Publishing Group
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Functional Epigenetics (IFE)
Grants SFB 1309
Helmholtz Gesellschaft
DFG
French Agence Nationale de la Recherche
University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS
GRAL
FRISBI