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PMID: 27627798 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Structural insights into the molecular mechanism of the m(6)A writer complex.

eLife ·Vol. 5 ·2016-00-14

Śledź P, Jinek M

Abstract

Methylation of adenosines at the N(6) position (m(6)A) is a dynamic and abundant epitranscriptomic mark that regulates critical aspects of eukaryotic RNA metabolism in numerous biological processes. The RNA methyltransferases METTL3 and METTL14 are components of a multisubunit m(6)A writer complex whose enzymatic activity is substantially higher than the activities of METTL3 or METTL14 alone. The molecular mechanism underpinning this synergistic effect is poorly understood. Here we report the crystal structure of the catalytic core of the human m(6)A writer complex comprising METTL3 and METTL14. The structure reveals the heterodimeric architecture of the complex and donor substrate binding by METTL3. Structure-guided mutagenesis indicates that METTL3 is the catalytic subunit of the complex, whereas METTL14 has a degenerate active site and plays non-catalytic roles in maintaining complex integrity and substrate RNA binding. These studies illuminate the molecular mechanism and evolutionary history of eukaryotic m(6)A modification in post-transcriptional genome regulation.

Keywords
RNA X-ray crystallography biochemistry biophysics epitranscriptomics human m6A methyltransferase post-transcriptional gene regulation structural biology
MeSH Terms
Crystallography, X-Ray Humans Methylation Methyltransferases/chemistry,genetics Multiprotein Complexes/chemistry,genetics Mutagenesis Protein Conformation RNA Cap-Binding Proteins/chemistry,genetics
Chemicals
Multiprotein Complexes RNA Cap-Binding Proteins METTL14 protein, human Methyltransferases METTL3 protein, human
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Śledź Paweł ORCID
Department of Biochemistry, University of Zurich, Zurich, Switzerland.
Jinek Martin ORCID
Department of Biochemistry, University of Zurich, Zurich, Switzerland.
Conflict of Interest

The authors declare that no competing interests exist.

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Article Info
Journal
eLife
Abbr.
Elife
ISSN
2050-084X
DOI
10.7554/eLife.18434
Published
2016-00-14
Epub
2016-00-14
Language
English
Region
England
NLM ID
101579614
PMCID
PMC5023411
Subset
IM
External Links
PubMed source DOI: 10.7554/eLife.18434 PMC Full Text View journal details
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