Structural basis of regulated m7G tRNA modification by METTL1–WDR4

Jiazhi Li, Longfei Wang, Quentin Hahn, Radosław P. Nowak, Thibault Viennet, Esteban A. Orellana, Shourya S. Roy Burman, Hong Yue, Moritz Hunkeler, Pietro Fontana, Hao Wu, Haribabu Arthanari, Eric S. Fischer and Richard I. Gregory ()
Additional contact information
Jiazhi Li: Boston Children’s Hospital
Longfei Wang: Harvard Medical School
Quentin Hahn: Boston Children’s Hospital
Radosław P. Nowak: Harvard Medical School
Thibault Viennet: Harvard Medical School
Esteban A. Orellana: Boston Children’s Hospital
Shourya S. Roy Burman: Harvard Medical School
Hong Yue: Harvard Medical School
Moritz Hunkeler: Harvard Medical School
Pietro Fontana: Harvard Medical School
Hao Wu: Harvard Medical School
Haribabu Arthanari: Harvard Medical School
Eric S. Fischer: Harvard Medical School
Richard I. Gregory: Boston Children’s Hospital

Nature, 2023, vol. 613, issue 7943, 391-397

Abstract: Abstract Chemical modifications of RNA have key roles in many biological processes1–3. N7-methylguanosine (m7G) is required for integrity and stability of a large subset of tRNAs4–7. The methyltransferase 1–WD repeat-containing protein 4 (METTL1–WDR4) complex is the methyltransferase that modifies G46 in the variable loop of certain tRNAs, and its dysregulation drives tumorigenesis in numerous cancer types8–14. Mutations in WDR4 cause human developmental phenotypes including microcephaly15–17. How METTL1–WDR4 modifies tRNA substrates and is regulated remains elusive18. Here we show, through structural, biochemical and cellular studies of human METTL1–WDR4, that WDR4 serves as a scaffold for METTL1 and the tRNA T-arm. Upon tRNA binding, the αC region of METTL1 transforms into a helix, which together with the α6 helix secures both ends of the tRNA variable loop. Unexpectedly, we find that the predicted disordered N-terminal region of METTL1 is part of the catalytic pocket and essential for methyltransferase activity. Furthermore, we reveal that S27 phosphorylation in the METTL1 N-terminal region inhibits methyltransferase activity by locally disrupting the catalytic centre. Our results provide a molecular understanding of tRNA substrate recognition and phosphorylation-mediated regulation of METTL1–WDR4, and reveal the presumed disordered N-terminal region of METTL1 as a nexus of methyltransferase activity.

Date: 2023
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DOI: 10.1038/s41586-022-05566-4

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