7U20

Crystal structure of human METTL1 and WDR4 complex

7U20 の概要

• エントリーDOI: 10.2210/pdb7u20/pdb
• 分子名称: tRNA (guanine-N(7)-)-methyltransferase, tRNA (guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: mettl1 wdr4 trna methyltransferase, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79167.72

構造登録者

Li, J.,Nowak, R.P.,Fischer, E.S.,Gregory, R. (登録日: 2022-02-22, 公開日: 2022-12-07, 最終更新日: 2023-10-25)

主引用文献

Li, J.,Wang, L.,Hahn, Q.,Nowak, R.P.,Viennet, T.,Orellana, E.A.,Roy Burman, S.S.,Yue, H.,Hunkeler, M.,Fontana, P.,Wu, H.,Arthanari, H.,Fischer, E.S.,Gregory, R.I.
Structural basis of regulated m 7 G tRNA modification by METTL1-WDR4.
Nature, 613:391-397, 2023

PubMed Abstract: Chemical modifications of RNA have key roles in many biological processes. N-methylguanosine (mG) is required for integrity and stability of a large subset of tRNAs. 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. Mutations in WDR4 cause human developmental phenotypes including microcephaly. How METTL1-WDR4 modifies tRNA substrates and is regulated remains elusive. 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.

PubMed: 36599985
DOI: 10.1038/s41586-022-05566-4

実験手法

X-RAY DIFFRACTION (3.1 Å)