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; Richard I. Gregory

doi:10.1038/s41586-022-05566-4

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, Richard I. Gregory^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

44 Citations (Scopus)

Abstract

Chemical modifications of RNA have key roles in many biological processes^1–3. N⁷-methylguanosine (m⁷G) is required for integrity and stability of a large subset of tRNAs^4–7. 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 types^8–14. Mutations in WDR4 cause human developmental phenotypes including microcephaly^15–17. 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.

Original language	English
Journal	Nature
Volume	613
Pages (from-to)	391-397
Number of pages	7
ISSN	0028-0836
DOIs	https://doi.org/10.1038/s41586-022-05566-4
Publication status	Published - 12 Jan 2023
Externally published	Yes

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title = "Structural basis of regulated m7G tRNA modification by METTL1–WDR4",

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.",

author = "Jiazhi Li and Longfei Wang and Quentin Hahn and Nowak, {Rados{\l}aw P.} and Thibault Viennet and Orellana, {Esteban A.} and {Roy Burman}, {Shourya S.} and Hong Yue and Moritz Hunkeler and Pietro Fontana and Hao Wu and Haribabu Arthanari and Fischer, {Eric S.} and Gregory, {Richard I.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

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doi = "10.1038/s41586-022-05566-4",

language = "English",

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T1 - Structural basis of regulated m7G tRNA modification by METTL1–WDR4

AU - Li, Jiazhi

AU - Wang, Longfei

AU - Hahn, Quentin

AU - Nowak, Radosław P.

AU - Viennet, Thibault

AU - Orellana, Esteban A.

AU - Roy Burman, Shourya S.

AU - Yue, Hong

AU - Hunkeler, Moritz

AU - Fontana, Pietro

AU - Wu, Hao

AU - Arthanari, Haribabu

AU - Fischer, Eric S.

AU - Gregory, Richard I.

PY - 2023/1/12

Y1 - 2023/1/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41586-022-05566-4

DO - 10.1038/s41586-022-05566-4

M3 - Journal article

C2 - 36599985

AN - SCOPUS:85145565295

SN - 0028-0836

VL - 613

SP - 391

EP - 397

JO - Nature

JF - Nature

ER -

Structural basis of regulated m⁷G tRNA modification by METTL1–WDR4

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