Visualization of chemical modifications in the human 80S ribosome structure

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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Figure 1: High-resolution structure of the human 80S ribosome.
Figure 2: Chemical modifications of the rRNA in the human 60S ribosomal subunit.
Figure 3: Chemical modifications of rRNA in the human 40S ribosomal subunit.
Figure 4: Chemical modifications in the vicinity of ligand-binding pockets of the human 80S ribosome with three bound inhibitors.
Figure 5: Role of chemical modifications and their evolutionary extension between prokaryotic and eukaryotic species.

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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.

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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.

Corresponding author

Correspondence to Bruno P. Klaholz.

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The authors declare no competing financial interests.

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

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Extended data figures and tables

Extended Data Figure 1 Particle sorting scheme.

The initial dataset (top) was sorted into two main 3D classes (+/− rotated) and particles of the non-rotated state were either split further, depending on whether tRNA is bound to the E site (absence of tRNA means CHX is bound), or subjected to focused refinement of the 60S subunit and the 40S subunit head and body parts.

Extended Data Figure 2 Focused refinement and resolution estimation.

a, Focused refinement of the 60S subunit and the 40S subunit head and body regions (left, entire 80S complex; right, central section). b, Sections through the individually refined regions during focused refinement (the individually refined areas are sharp, whereas the other regions are less ordered). c, Individually refined regions in the 80S structure. d, Resolution estimation from the FSC curves.

Extended Data Figure 3 Representative regions in the 60S and 40S ribosomal subunits.

ad, Cryo-EM map and atomic model of various regions in the 60S subunit. eh, Cryo-EM map and atomic model of various regions in the 40S subunit.

Extended Data Figure 4 Register shift examples in previously less ordered rRNA regions.

af, Comparison of the previous map and previous atomic model23 (top), with the new map and the previous model (middle), and the new map with the refined atomic model after correction of register shifts.

Extended Data Figure 5 Specific features in the human ribosome structure.

ac, Reannotation of an rRNA region as a ribosomal protein (eL29). d, Protein modifications on two lysine residues. eh, Analysis of rRNA modifications in the 5.8S rRNA including sub-stoichiometric modification of Um14. i, j, Comparisons of neighbouring residues with and without rRNA modifications (human 60S and 40S ribosomal subunits, respectively).

Extended Data Figure 6 Annotation of chemical modifications in the 60S ribosomal subunit.

Conserved sites in E. coli and human large ribosomal subunits (magenta), predicted and found sites (cyan), unpredicted 2′-O-Me modification sites (blue), unpredicted base modification sites (red) and a 5.8S rRNA modification (green).

Extended Data Figure 7 Detailed views of the chemical modifications in the 60S ribosomal subunit (class I and class II).

Individual modification sites in classes I and II (magenta and cyan, respectively; cyan arrows indicate 2′-O-ribose methylations, black arrows indicate Ψs validated through the specific hydrogen-bond pattern, other modifications are indicated with magenta arrows).

Extended Data Figure 8 Detailed views of the chemical modifications in the 60S ribosomal subunit (class III).

Individual modification sites in class III (red; arrow colours as in Extended Data Fig. 7).

Extended Data Figure 9 Annotation of chemical modifications in the 40S ribosomal subunit.

Conserved sites in E. coli and human (magenta), predicted and found sites (cyan), unpredicted 2′-O-Me modification sites (blue) and unpredicted base modification sites (red).

Extended Data Figure 10 Detailed views of the chemical modifications in the 40S ribosomal subunit (classes I, II and III).

Individual modification sites in classes I, II and III (in magenta, cyan and red, respectively; arrow colours as in Extended Data Fig. 7).

Extended Data Figure 11 rRNA modifications in E. coli and human ribosomal subunits.

a, Large ribosomal subunit (left, E. coli; right, human). b, Small ribosomal subunit (left, E. coli; right, human).

Extended Data Table 1 Data, statistics and classification of rRNA modifications

Supplementary information

Life Sciences Reporting Summary

Supplementary Table 1

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

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).

Supplementary Table 3

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

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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Natchiar, S., Myasnikov, A., Kratzat, H. et al. Visualization of chemical modifications in the human 80S ribosome structure. Nature 551, 472–477 (2017). https://doi.org/10.1038/nature24482

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