7RX7

Structure of METTL3-METTL14(R298P) mutant methyltransferase complex

7RX7 の概要

• エントリーDOI: 10.2210/pdb7rx7/pdb
• 分子名称: N6-adenosine-methyltransferase 70 kDa subunit, N6-adenosine-methyltransferase non-catalytic subunit (3 entities in total)
• 機能のキーワード: rna methyltransferase complex, mutant, 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: 65246.13

構造登録者

Wang, P.,Nam, Y. (登録日: 2021-08-21, 公開日: 2022-11-09, 最終更新日: 2026-01-14)

主引用文献

Zhang, C.,Scott, R.L.,Tunes, L.,Hsieh, M.H.,Wang, P.,Kumar, A.,Khadgi, B.B.,Yang, Y.Y.,Doxtader Lacy, K.A.,Herrell, E.,Zhang, X.,Evers, B.,Wang, Y.,Xing, C.,Zhu, H.,Nam, Y.
Cancer mutations rewire the RNA methylation specificity of METTL3-METTL14.
Sci Adv, 10:eads4750-eads4750, 2024

PubMed Abstract: Chemical modification of RNAs is important for posttranscriptional gene regulation. The METTL3-METTL14 complex generates most -methyladenosine (mA) modifications in messenger RNAs (mRNAs), and dysregulated methyltransferase expression has been linked to cancers. Here we show that a changed sequence context for mA can promote oncogenesis. A gain-of-function missense mutation from patients with cancer, METTL14, increases malignant cell growth in culture and transgenic mice without increasing global mA levels in mRNAs. The mutant methyltransferase preferentially modifies noncanonical sites containing a GGAU motif, in vitro and in vivo. The mA in GGAU context is detected by the YTH family of readers similarly to the canonical sites but is demethylated less efficiently by an eraser, ALKBH5. Combining the biochemical and structural data, we provide a model for how the cognate RNA sequences are selected for methylation by METTL3-METTL14. Our work highlights that sequence-specific mA deposition is important and that increased GGAU methylation can promote oncogenesis.

PubMed: 39705353
DOI: 10.1126/sciadv.ads4750

実験手法

X-RAY DIFFRACTION (1.645 Å)