Letter | Published:

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

Nature volume 534, pages 575578 (23 June 2016) | Download Citation

  • A Corrigendum to this article was published on 18 January 2017

Abstract

Chemical modifications of RNA have essential roles in a vast range of cellular processes1,2,3. N6-methyladenosine (m6A) 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, respectively2,3,4,5. An MTase complex comprising methyltransferase-like 3 (METTL3) and methyltransferase-like 14 (METTL14) efficiently catalyses methyl group transfer6,7. In contrast to the well-studied DNA MTase8, 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 Å, 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 m6A 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 N6-adenine MTase9,10. This structural information provides an important framework for the functional investigation of m6A.

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Data deposits

The atomic coordinates and structure factors for the reported crystal structures have been deposited in the Protein Data Bank (PDB) with the accession codes 5IL0 (ligand-free form), 5IL1 (AdoMet-bound form) and 5IL2 (AdoHcy-bound form).

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Acknowledgements

We thank B. Sun (SSRF beamline BL17U), R. Zhang (BL19U1), and N. Li (BL19U2) for on-site assistance; S. Fan for data collection support; and research associates at the Center for Protein Research, Huazhong Agricultural University, for technical support. This work was supported by funds from the Ministry of Science and Technology (grants 2015CB910900 and 2013CB910200), Fok Ying-Tong Education Foundation (grant 151021), the Fundamental Research Funds for the Central Universities (Program No. 2014PY026, No. 2015PY219, and No. 2014JQ001), and Huazhong Agricultural University Scientific & Technological Self-innovation Foundation (Program No. 2013RC013).

Author information

Author notes

    • Xiang Wang
    • , Jing Feng
    •  & Yuan Xue

    These authors contributed equally to this work.

Affiliations

  1. National Key Laboratory of Crop Genetic Improvement and National Centre of Plant Gene Research, Huazhong Agricultural University, Wuhan 430070, China

    • Xiang Wang
    • , Jing Feng
    • , Yuan Xue
    • , Zeyuan Guan
    • , Delin Zhang
    • , Qiang Wang
    • , Jinbo Huang
    • , Tingting Zou
    •  & Ping Yin
  2. Department of Pharmacology, Zhejiang University, School of Medicine, Hangzhou 310028, China

    • Zhu Liu
    •  & Chun Tang
  3. CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, National Center for Magnetic Resonance at Wuhan, Wuhan Institute of Physics and Mathematics of the Chinese Academy of Sciences, Wuhan 430071, China

    • Zhou Gong
    •  & Chun Tang
  4. College of Life Sciences and Technology, Huazhong Agricultural University, Wuhan 430070, China

    • Tingting Zou

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Contributions

X.W., T.Z. and P.Y. designed all experiments. X.W., J.F. and Y.X. performed protein purification and crystallization. Z.Gu. determined all of the structures. X.W., Z.L., Z.Go., Q.W., D.Z., J.H., C.T., T.Z. and P.Y. performed the biochemical assays. All authors analysed the data and contributed to manuscript preparation. X.W., T.Z. and P.Y. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ping Yin.

Reviewer Information Nature thanks M. Helm, W. Versées and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Figure

    This file contains Supplementary Figure 1, the uncropped gel images for Extended Data Figure 6a.

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DOI

https://doi.org/10.1038/nature18298

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