Author
Listed:
- Jiazhi Li
(Boston Children’s Hospital
Harvard Medical School
Dana-Farber Cancer Institute)
- Longfei Wang
(Harvard Medical School
Boston Children’s Hospital
Wuhan University)
- Quentin Hahn
(Boston Children’s Hospital)
- Radosław P. Nowak
(Harvard Medical School
Dana-Farber Cancer Institute)
- Thibault Viennet
(Harvard Medical School
Dana-Farber Cancer Institute)
- Esteban A. Orellana
(Boston Children’s Hospital
Harvard Medical School)
- Shourya S. Roy Burman
(Harvard Medical School
Dana-Farber Cancer Institute)
- Hong Yue
(Harvard Medical School
Dana-Farber Cancer Institute)
- Moritz Hunkeler
(Harvard Medical School
Dana-Farber Cancer Institute)
- Pietro Fontana
(Harvard Medical School
Boston Children’s Hospital)
- Hao Wu
(Harvard Medical School
Boston Children’s Hospital)
- Haribabu Arthanari
(Harvard Medical School
Dana-Farber Cancer Institute)
- Eric S. Fischer
(Harvard Medical School
Dana-Farber Cancer Institute)
- Richard I. Gregory
(Boston Children’s Hospital
Harvard Medical School
Boston Children’s Hospital
Harvard Medical School)
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.
Suggested Citation
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, 2023.
"Structural basis of regulated m7G tRNA modification by METTL1–WDR4,"
Nature, Nature, vol. 613(7943), pages 391-397, January.
Handle:
RePEc:nat:nature:v:613:y:2023:i:7943:d:10.1038_s41586-022-05566-4
DOI: 10.1038/s41586-022-05566-4
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