Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases

By Ping-yuan Wang, K. Doxtader, Y. Nam. Molecules and Cells, 2016

1,106 citations recorded by the source corpus.

Summary N6-methyladenosine (m6A) is a prevalent, reversible chemical modification of functional RNAs, and is important for central events in biology. The core m6A writers are Mettl3 and Mettl14, which both contain methyltransferase domains. How Mettl3 and Mettl14 cooperate to catalyze methylation of adenosines has remained elusive. We present crystal structures of the complex of Mettl3/Mettl14 methyltransferase domains in apo form as well as with bound S-adenosylmethionine (SAM) or S-adenosylhomocysteine (SAH) in the catalytic site. We determine that the heterodimeric complex of methyltransferase domains, combined with CCCH motifs constitute the minimally required regions for creating m6A modifications in vitro. We also show that Mettl3 is the catalytically active subunit while Mettl14 plays a structural role critical for substrate recognition. Our model provides a molecular explanation for why certain mutations of Mettl3 and Mettl14 lead to impaired function of the methyltransferase complex.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c9e1b2e8b69060a75911db21d7f1ab640132d2d0

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In Molecular Biology

1. Chuan He
2. Samie R. Jaffrey
3. Kate D. Meyer
4. Hailing Shi
5. Jiangbo W
6. Jianjun Chen
7. B. Zhao
8. Zhike Lu

Citations in the corpus

• YTH Domain: A Family of N6-methyladenosine (m6A) Readers (2018, background): “Although both METTL3 and METTL14 adopt a canonical fold similar to that of other methyltransferases [20], only METTL3 can bind to the methyl donor Sadenosyl methionine (SAM or AdoMet), whereas METTL14 acts to modulate the activity of METTL3 and binds to the RNA substrate instead [20,24,25].”
• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “, 2013)— the former as the catalytic subunit and the latter as an essential component to facilitate RNA binding (Wang et al., 2016a; Wang et al., 2016b).”
• Methylation multiplicity and its clinical values in cancer (2021, positive): “METTL14 could enhance the catalytic activity of METTL3 via forming heterodimers with METTL3 with the ratio of 1:1 (Refs 21, 22).”
• Functions of N6-methyladenosine and its role in cancer (2019, background): “METTL14 forms a stable complex with METTL3 and plays a key role in substrate recognition [13, 14, 38].”
• METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification (2017, background): “…of wild-type (METTL14-WT), but not mutated METTL14 (METTL14-R298P; R298 is critical for target recognition of the methyltransferase complex [Wang et al., 2016a, 2016b]), substantially increased global m6A level and promoted cell immortalization mediated by MA9 (Figures 3B and 3C),…”
• Rethinking m6A Readers, Writers, and Erasers (2017, background): “R298P, which is detected in uterine/ endometrial cancers, is a mutation in the RNA-binding domain, and the mutated form of METTL14 shows partially reduced methyltransferase activity, most likely due to inefficient RNA binding (P. Wang et al. 2016).”
• The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal and leukemia cells (2017, neutral): “3d and Supplementary Tables 5– 11).”
• Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell self-renewal (2018, background): “The crystal structure of the METTL3 and METTL14 complex suggests that METTL3 is the catalytic component while METTL14, which forms a heterodimer with METTL3, contributes to substrate RNA binding (Wang et al., 2016a; Wang et al., 2016b).”