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Structural basis of N6-adenosine methylation by the METTL3–METTL14 complex

Chemical modifications of RNA have essential roles in a vast range of cellular processes (1-3). [N.sup.6]-methyladenosine ([m.sup.6]A) is an abundant internal modification in messenger RNA and long non-coding RNA that can be dynamically added and removed by RNA methyltransferases (MTases) and demeth... Full description

Journal Title: Nature 2016
Main Author: Xiang Wang
Other Authors: Jing Feng , Yuan Xue , Zeyuan Guan , Delin Zhang , Zhu Liu , Zhou Gong , Qiang Wang , Jinbo Huang , Chun Tang , Tingting Zou , Ping Yin
Format: Electronic Article Electronic Article
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ID: ISSN: 0028-0836 ; E-ISSN: 1476-4687 ; DOI: 10.1038/nature18298
Link: http://dx.doi.org/10.1038/nature18298
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recordid: nature_a10.1038/nature18298
title: Structural basis of N6-adenosine methylation by the METTL3–METTL14 complex
format: Article
creator:
  • Xiang Wang
  • Jing Feng
  • Yuan Xue
  • Zeyuan Guan
  • Delin Zhang
  • Zhu Liu
  • Zhou Gong
  • Qiang Wang
  • Jinbo Huang
  • Chun Tang
  • Tingting Zou
  • Ping Yin
subjects:
  • Methyltransferases -- Chemical Properties
  • Methyltransferases -- Analysis
  • Crystal Structure -- Analysis
  • Messenger Rna -- Research
  • Methylation -- Analysis
ispartof: Nature, 2016
description: Chemical modifications of RNA have essential roles in a vast range of cellular processes (1-3). [N.sup.6]-methyladenosine ([m.sup.6]A) is an abundant internal modification in messenger RNA and long non-coding RNA that can be dynamically added and removed by RNA methyltransferases (MTases) and demethylases, respectively (2-5). An MTase complex comprising methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14) efficiently catalyses methyl group transfer (6,7). In contrast to the well-studied DNA MTase (8), the exact roles of these two RNA MTases in the complex remain to be elucidated. Here we report the crystal structures of the METTL3-METTL14 heterodimer with MTase domains in the ligand-free, S-adenosyl methionine (AdoMet)-bound and S-adenosyl homocysteine (AdoHcy)-bound states, with resolutions of 1.9, 1.71 and 1.61 [Angstrom], respectively. Both METTL3 and METTL14 adopt a class I MTase fold and they interact with each other via an extensive hydrogen bonding network, generating a positively charged groove. Notably, AdoMet was observed in only the METTL3 pocket and not in METTL14. Combined with biochemical analysis, these results suggest that in the [m.sup.6]A MTase complex, METTL3 primarily functions as the catalytic core, while METTL14 serves as an RNA-binding platform, reminiscent of the target recognition domain of DNA [N.sup.6]-adenine MTase (9,10). This structural information provides an important framework for the functional investigation of [m.sup.6]A.
language:
source:
identifier: ISSN: 0028-0836 ; E-ISSN: 1476-4687 ; DOI: 10.1038/nature18298
fulltext: fulltext
issn:
  • 0028-0836
  • 00280836
  • 1476-4687
  • 14764687
url: Link


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titleStructural basis of N6-adenosine methylation by the METTL3–METTL14 complex
creatorXiang Wang ; Jing Feng ; Yuan Xue ; Zeyuan Guan ; Delin Zhang ; Zhu Liu ; Zhou Gong ; Qiang Wang ; Jinbo Huang ; Chun Tang ; Tingting Zou ; Ping Yin
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descriptionChemical modifications of RNA have essential roles in a vast range of cellular processes (1-3). [N.sup.6]-methyladenosine ([m.sup.6]A) is an abundant internal modification in messenger RNA and long non-coding RNA that can be dynamically added and removed by RNA methyltransferases (MTases) and demethylases, respectively (2-5). An MTase complex comprising methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14) efficiently catalyses methyl group transfer (6,7). In contrast to the well-studied DNA MTase (8), the exact roles of these two RNA MTases in the complex remain to be elucidated. Here we report the crystal structures of the METTL3-METTL14 heterodimer with MTase domains in the ligand-free, S-adenosyl methionine (AdoMet)-bound and S-adenosyl homocysteine (AdoHcy)-bound states, with resolutions of 1.9, 1.71 and 1.61 [Angstrom], respectively. Both METTL3 and METTL14 adopt a class I MTase fold and they interact with each other via an extensive hydrogen bonding network, generating a positively charged groove. Notably, AdoMet was observed in only the METTL3 pocket and not in METTL14. Combined with biochemical analysis, these results suggest that in the [m.sup.6]A MTase complex, METTL3 primarily functions as the catalytic core, while METTL14 serves as an RNA-binding platform, reminiscent of the target recognition domain of DNA [N.sup.6]-adenine MTase (9,10). This structural information provides an important framework for the functional investigation of [m.sup.6]A.
subjectMethyltransferases -- Chemical Properties ; Methyltransferases -- Analysis ; Crystal Structure -- Analysis ; Messenger Rna -- Research ; Methylation -- Analysis;
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titleStructural basis of N6-adenosine methylation by the METTL3–METTL14 complex
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