7RX7

Structure of METTL3-METTL14(R298P) mutant methyltransferase complex

Summary for 7RX7

• Entry DOI: 10.2210/pdb7rx7/pdb
• Descriptor: N6-adenosine-methyltransferase 70 kDa subunit, N6-adenosine-methyltransferase non-catalytic subunit (3 entities in total)
• Functional Keywords: rna methyltransferase complex, mutant, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 65246.13

Authors

Wang, P.,Nam, Y. (deposition date: 2021-08-21, release date: 2022-11-09, Last modification date: 2026-01-14)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.645 Å)