Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases

Ping Wang, Katelyn A. Doxtader, Yunsun Nam

Research output: Contribution to journalArticle

164 Citations (Scopus)

Abstract

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, constitutes 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.

Original languageEnglish (US)
Pages (from-to)306-317
Number of pages12
JournalMolecular Cell
Volume63
Issue number2
DOIs
StatePublished - Jul 21 2016

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Methyltransferases
S-Adenosylhomocysteine
S-Adenosylmethionine
Adenosine
Methylation
Catalytic Domain
RNA
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases. / Wang, Ping; Doxtader, Katelyn A.; Nam, Yunsun.

In: Molecular Cell, Vol. 63, No. 2, 21.07.2016, p. 306-317.

Research output: Contribution to journalArticle

Wang, Ping ; Doxtader, Katelyn A. ; Nam, Yunsun. / Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases. In: Molecular Cell. 2016 ; Vol. 63, No. 2. pp. 306-317.
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