@article{34465696933847a5a43594c85b3e3b8b,
title = "Structural Basis for Regulation of METTL16, an S-Adenosylmethionine Homeostasis Factor",
abstract = " 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 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. Doxtader et al. determine crystal structures of the N 6 -methyladenosine methyltransferase METTL16 in complex with RNA substrates. METTL16 can be regulated by the conformation of the RNA substrate and by an autoregulatory loop near the SAM binding pocket. Modulating the catalytic activity of METTL16 changes MAT2A mRNA levels in cells. ",
keywords = "MAT2A, METTL14, METTL16, METTL3, N6-methyladenosine (m6A), S-adenosylmethionine (SAM), SAM homeostasis, metabolism, methyltransferase",
author = "Doxtader, {Katelyn A.} and Ping Wang and Scarborough, {Anna M.} and Dahee Seo and Conrad, {Nicholas K.} and Yunsun Nam",
note = "Funding Information: We thank support from the Cecil H. and Ida Green Center Training Program in Reproductive Biology Sciences Research and also members of the Structural Biology Laboratory at UT Southwestern for help with data collection. Y.N. is a Southwestern Medical Foundation Scholar in Biomedical Research ( Endowed Scholar Program at UT Southwestern ), a Pew Scholar ( 27339 ), and a Packard Fellow ( 2013-39275 ). This study was supported by grants from the NIH NIGMS ( R01GM122960 to Y.N., 2T32GM008297 to K.A.D., and 5T32GM007062 to A.M.S.), American Heart Association ( 17POST33410713 to P.W.), the Welch Foundation ( I-1851-20170325 to Y.N. and I-1915-20170325 to N.K.C.), Cancer Prevention Research Institute of Texas ( R1221 ), and American Cancer Society/Harold C. Simmons Comprehensive Cancer Center ( ACS-IRG-02-196 to Y.N. and RSG-14-064-01-RMC to N.K.C.). The use of SBC 19ID beamline at Advanced Photon Source is supported by United States Department of Energy contract DE-AC02-06CH11357 . Funding Information: We thank support from the Cecil H. and Ida Green Center Training Program in Reproductive Biology Sciences Research and also members of the Structural Biology Laboratory at UT Southwestern for help with data collection. Y.N. is a Southwestern Medical Foundation Scholar in Biomedical Research (Endowed Scholar Program at UT Southwestern), a Pew Scholar (27339), and a Packard Fellow (2013-39275). This study was supported by grants from the NIH NIGMS (R01GM122960 to Y.N., 2T32GM008297 to K.A.D., and 5T32GM007062 to A.M.S.), American Heart Association (17POST33410713 to P.W.), the Welch Foundation (I-1851-20170325 to Y.N. and I-1915-20170325 to N.K.C.), Cancer Prevention Research Institute of Texas (R1221), and American Cancer Society/Harold C. Simmons Comprehensive Cancer Center (ACS-IRG-02-196 to Y.N. and RSG-14-064-01-RMC to N.K.C.). The use of SBC 19ID beamline at Advanced Photon Source is supported by United States Department of Energy contract DE-AC02-06CH11357. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = sep,
day = "20",
doi = "10.1016/j.molcel.2018.07.025",
language = "English (US)",
volume = "71",
pages = "1001--1011.e4",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}