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Title: Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases

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. Here, 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.

Authors:
; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC); Southwestern Medical Foundation; National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); Welch Foundation; Cancer Prevention and Research Institute of Texas (CPRIT); American Cancer Society; Harold C. Simmons Comprehensive Cancer Center
OSTI Identifier:
1393677
Alternate Identifier(s):
OSTI ID: 1274763
Grant/Contract Number:  
2T32GM008297; I-1851; R1221; ACS-IRG-02-196; AC02-06CH11357
Resource Type:
Published Article
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Name: Molecular Cell Journal Volume: 63 Journal Issue: 2; Journal ID: ISSN 1097-2765
Publisher:
Cell Press - Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Wang, Ping, Doxtader, Katelyn A., and Nam, Yunsun. Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases. United States: N. p., 2016. Web. doi:10.1016/j.molcel.2016.05.041.
Wang, Ping, Doxtader, Katelyn A., & Nam, Yunsun. Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases. United States. https://doi.org/10.1016/j.molcel.2016.05.041
Wang, Ping, Doxtader, Katelyn A., and Nam, Yunsun. Thu . "Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases". United States. https://doi.org/10.1016/j.molcel.2016.05.041.
@article{osti_1393677,
title = {Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases},
author = {Wang, Ping and Doxtader, Katelyn A. and Nam, Yunsun},
abstractNote = {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. Here, 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.},
doi = {10.1016/j.molcel.2016.05.041},
journal = {Molecular Cell},
number = 2,
volume = 63,
place = {United States},
year = {2016},
month = {6}
}

Journal Article:
Free Publicly Available Full Text
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https://doi.org/10.1016/j.molcel.2016.05.041

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