Article | Published:

Visualization of chemical modifications in the human 80S ribosome structure

Nature volume 551, pages 472477 (23 November 2017) | Download Citation

Abstract

Chemical modifications of human ribosomal RNA (rRNA) are introduced during biogenesis and have been implicated in the dysregulation of protein synthesis, as is found in cancer and other diseases. However, their role in this phenomenon is unknown. Here we visualize more than 130 individual rRNA modifications in the three-dimensional structure of the human ribosome, explaining their structural and functional roles. In addition to a small number of universally conserved sites, we identify many eukaryote- or human-specific modifications and unique sites that form an extended shell in comparison to bacterial ribosomes, and which stabilize the RNA. Several of the modifications are associated with the binding sites of three ribosome-targeting antibiotics, or are associated with degenerate states in cancer, such as keto alkylations on nucleotide bases reminiscent of specialized ribosomes. This high-resolution structure of the human 80S ribosome paves the way towards understanding the role of epigenetic rRNA modifications in human diseases and suggests new possibilities for designing selective inhibitors and therapeutic drugs.

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Acknowledgements

We thank J. Michalon, R. Fritz and R. David for IT support, J.-F. Ménétret for technical support, M.-C. Poterszman for constant support, the IGBMC cell culture facilities for HeLa cell production, and B. Beinsteiner for making the 3D animation. We thank D. Agard and S. Zheng for making MotionCor2 available ahead of publication. This work was supported by CNRS, Association pour la Recherche sur le Cancer (ARC), Institut National du Cancer (INCa), Ligue nationale contre le cancer (Ligue), Agence National pour la Recherche (ANR; ANR-10-LABX-0030-INRT under the program Investissements d’Avenir ANR-10-IDEX-0002-02). The electron microscope facility was supported by the Alsace Region, the Fondation pour la Recherche Médicale (FRM), Inserm, CNRS and ARC, by Instruct-ULTRA as part of the European Union’s Horizon 2020 (grant ID 731005), the French Infrastructure for Integrated Structural Biology (FRISBI; ANR-10-INSB-05-01) and by Instruct-ERIC.

Author information

Author notes

    • Hanna Kratzat

    Present address: Gene Center, Ludwig-Maximilians-Universität, Munich, Germany.

    • S. Kundhavai Natchiar
    •  & Alexander G. Myasnikov

    These authors contributed equally to this work.

Affiliations

  1. Centre for Integrative Biology (CBI), Department of Integrated Structural Biology, IGBMC, CNRS, Inserm, Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France

    • S. Kundhavai Natchiar
    • , Alexander G. Myasnikov
    • , Hanna Kratzat
    • , Isabelle Hazemann
    •  & Bruno P. Klaholz
  2. Institute of Genetics and of Molecular and Cellular Biology (IGBMC), 1 rue Laurent Fries, Illkirch, France

    • S. Kundhavai Natchiar
    • , Alexander G. Myasnikov
    • , Hanna Kratzat
    • , Isabelle Hazemann
    •  & Bruno P. Klaholz
  3. Centre National de la Recherche Scientifique (CNRS), UMR 7104, Illkirch, France

    • S. Kundhavai Natchiar
    • , Alexander G. Myasnikov
    • , Hanna Kratzat
    • , Isabelle Hazemann
    •  & Bruno P. Klaholz
  4. Institut National de la Santé et de la Recherche Médicale (Inserm), U964, Illkirch, France

    • S. Kundhavai Natchiar
    • , Alexander G. Myasnikov
    • , Hanna Kratzat
    • , Isabelle Hazemann
    •  & Bruno P. Klaholz
  5. Université de Strasbourg, Illkirch, France

    • S. Kundhavai Natchiar
    • , Alexander G. Myasnikov
    • , Hanna Kratzat
    • , Isabelle Hazemann
    •  & Bruno P. Klaholz

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Contributions

I.H. performed sample preparation, A.G.M. acquired cryo-EM data, A.G.M., H.K. and S.K.N. performed image processing, S.K.N. did structure refinement and model building, and S.K.N. and B.P.K. performed structural analysis of the rRNA. All authors analysed the data. B.P.K supervised the project and wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bruno P. Klaholz.

Reviewer Information Nature thanks J. D. Dinman and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    This file contains universally conserved sites (Class I) and bacteria-specific sites.

  2. 2.

    Supplementary Table 2

    This file contains predicted sites (Class II) visible in the human ribosome structure and 2’-O-methylation (Am, Cm, Gm, Um); methylation at various at atomic positions (mn); pseudo-uridylation Ψ (not counting other predicted sites); aminocarboxypropylation (acp).

  3. 3.

    Supplementary Table 3

    This file contains unpredicted human specific modifications (Class III) and a list sorted according to increasing residue numbers (Class III):

Videos

  1. 1.

    3D video of the human ribosome structure

    The 3D video of the human ribosome structure shows the overall structure with the cryo-EM map (blue mesh) and the atomic model, then the full set of rRNA modifications and some more detailed examples of the 3 classes of rRNA modifications.

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https://doi.org/10.1038/nature24482

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