Molecular Cell
Volume 71, Issue 6, 20 September 2018, Pages 1001-1011.e4
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Article
Structural Basis for Regulation of METTL16, an S-Adenosylmethionine Homeostasis Factor

https://doi.org/10.1016/j.molcel.2018.07.025Get rights and content
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Highlights

  • METTL16 recognizes substrate RNA sequence and structure for methylation

  • Methylation activity of METTL16 can be modulated by the substrate RNA conformation

  • METTL16 is autoregulated through its SAM binding pocket

  • Mutations in the catalytic domain of METTL16 regulate MAT2A mRNA levels in cells

Summary

S-adenosylmethionine (SAM) is an essential metabolite that acts as a cofactor for most methylation events in the cell. The N6-methyladenosine (m6A) methyltransferase METTL16 controls SAM homeostasis by regulating the abundance of SAM synthetase MAT2A mRNA in response to changing intracellular SAM levels. Here we present crystal structures of METTL16 in complex with MAT2A RNA hairpins to uncover critical molecular mechanisms underlying the regulated activity of METTL16. The METTL16-RNA complex structures reveal atomic details of RNA substrates that drive productive methylation by METTL16. In addition, we identify a polypeptide loop in METTL16 near the SAM binding site with an autoregulatory role. We show that mutations that enhance or repress METTL16 activity in vitro correlate with changes in MAT2A mRNA levels in cells. Thus, we demonstrate the structural basis for the specific activity of METTL16 and further suggest the molecular mechanisms by which METTL16 efficiency is tuned to regulate SAM homeostasis.

Keywords

METTL16
N6-methyladenosine (m6A)
S-adenosylmethionine (SAM)
methyltransferase
MAT2A
SAM homeostasis
METTL3
METTL14
metabolism

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