期刊
MOLECULAR CELL
卷 71, 期 6, 页码 1001-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2018.07.025
关键词
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资金
- NIH NIGMS [R01GM122960, 2T32GM008297, 5T32GM007062]
- American Heart Association [17POST33410713]
- Welch Foundation [I-1851-20170325, 1915-20170325]
- Cancer Prevention Research Institute of Texas [R1221]
- American Cancer Society/Harold C. Simmons Comprehensive Cancer Center [ACS-IRG-02-196, RSG-14-064-01-RMC]
- United States Department of Energy [DE-AC02-06CH11357]
- Cecil H. and Ida Green Center Training Program in Reproductive Biology Sciences Research
S-adenosylmethionine (SAM) is an essential metabolite that acts as a cofactor for most methylation events in the cell. The N-6-methyladenosine (m(6)A) 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 withMAT2A 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.
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