Structural insights into assembly, operation and inhibition of a type I restriction–modification system

Abstract

Type I restriction–modification (R–M) systems are widespread in prokaryotic genomes and provide robust protection against foreign DNA. They are multisubunit enzymes with methyltransferase, endonuclease and translocase activities. Despite extensive studies over the past five decades, little is known about the molecular mechanisms of these sophisticated machines. Here, we report the cryo-electron microscopy structures of the representative EcoR124I R–M system in different assemblies (R2M2S1, R1M2S1 and M2S1) bound to target DNA and the phage and mobile genetic element-encoded anti-restriction proteins Ocr and ArdA. EcoR124I can precisely regulate different enzymatic activities by adopting distinct conformations. The marked conformational transitions of EcoR124I are dependent on the intrinsic flexibility at both the individual-subunit and assembled-complex levels. Moreover, Ocr and ArdA use a DNA-mimicry strategy to inhibit multiple activities, but do not block the conformational transitions of the complexes. These structural findings, complemented by mutational studies of key intermolecular contacts, provide insights into assembly, operation and inhibition mechanisms of type I R–M systems.

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Fig. 1: Structures of M2S1 methyltransferase bound to DNA and ArdA.
Fig. 2: Structures of R2M2S1 bound to DNA, Ocr or ArdA in the translocation state.
Fig. 3: Structures of R2M2S1 bound to DNA or Ocr in the intermediate state.
Fig. 4: Structures of R1M2S1 bound to DNA, Ocr or ArdA in the RAS.
Fig. 5: Intrinsic flexibility of individual subunits and conformational changes of Ocr and ArdA dimers.
Fig. 6: Working model for type I R–M holoenzymes.

Data availability

Data supporting the findings of this manuscript are available from the corresponding authors upon reasonable request. The source data underlying Figs. 1g,h, 2g,h, 3f,g and 5b and Extended Data Figs. 1a–c and 9e–g are provided with the article and in the Supplementary Information files. Atomic coordinates have been deposited at the Protein Data Bank under accession numbers 7BTR (R1M2S1-ArdARAS), 7BTQ (R1M2S1-DNARAS), 7BST (R2M2S1-OCRIS), 7BTP (R1M2S1-OCRRAS) and 7BTO (R2M2S1–ArdATS), and cryo-EM density maps have been deposited at the Electron Microscopy Data Bank under accession numbers EMDB-30183 (R1M2S1-ArdARAS); EMDB-30182 (R1M2S1-DNARAS); EMDB-30166 (R2M2S1-OCRIS); EMDB-30180 (R2M2S1-ArdATS); EMDB-30181 (R1M2S1-OCRRAS); EMDB-30184 (R2M2S1-OCRTS); EMDB-30185 (R2M2S1-DNAIS); EMDB-30186 (R2M2S1-DNATS); EMDB-30187 (M2S1-DNA) and EMDB-30188 (M2S1-ArdA).

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Acknowledgements

Cryo-EM data collection was carried out at the Center for Biological Imaging, Core Facilities for Protein Science at the Institute of Biophysics, Chinese Academy of Sciences. We thank B. Zhu, X. Huang, G. Ji, D. Fan, T. Niu, F. Sun and other staff members at the Center for Biological Imaging for their support in data collection; L. Kong for cryo-EM data storage and backup; A. Gao for the critical reading and helpful discussion. The project was funded by the National Key R&D Program of China (grant nos. 2018YFA0508000, 2018YFA0507203 and 2017YFA0504700), National Natural Science Foundation of China (grant nos. 91753133, 31670903 and 31570874) and the Strategic Priority Research Program at the Chinese Academy of Sciences (grant nos. XDB37030203 and XDB37040101). D.C. is sponsored by the Youth Innovation Promotion Association at the Chinese Academy of Sciences. P.G. and X.Z. received scholarships from the ‘National Thousand Young Talents Program’.

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Authors

Contributions

Y.G. and D.C. conducted the structural and biochemical experiments with the help of J.Z., H.F., X.L., X.-X.Y. and S.L. X.Z. and P.G. wrote the manuscript with the help of the other authors. P.G. initiated the project. X.Z. and P.G. directed the research.

Corresponding authors

Correspondence to Xinzheng Zhang or Pu Gao.

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Extended data

Extended Data Fig. 1 Purification of various EcoR124I complexes.

a-c, Elution profiles of SEC runs on Superdex 200 10/300 column and SDS-PAGE results of indicated fractions for M2S1 MTase and R2M2S1 holoenzyme (a), M2S1 bound to DNA/ArdA (b), and R2M2S1 bound to DNA/Ocr/ArdA (c). Experiments were performed three times independently with similar results. Source data

Extended Data Fig. 2 Single particle cryo-EM analysis of M2S1 MTase bound to DNA and ArdA.

a,b, Single particle cryo-EM analysis of M2S1-DNA (a) and M2S1-ArdA (b). Representative cryo-EM micrographs of M2S1-DNA (a-i) and M2S1-ArdA (b-i); Representative reference-free 2D-class averages of M2S1-DNA (a-ii) and M2S1-ArdA (b-ii); Data-processing workflows for M2S1-DNA (a-iii) and M2S1-ArdA (b-iii); The gold standard Fourier shell correlation (FSC) curves of M2S1-DNA (a-iv) and M2S1-ArdA (b-iv). Experiments were performed two times independently with similar results.

Extended Data Fig. 3 Single particle cryo-EM analysis of R2M2S1 bound to 44bp DNA.

a, Representative cryo-EM micrograph of R2M2S1-DNA (44 bp). Experiments were performed two times independently with similar results. b, Representative reference-free 2D-class averages. Experiments were performed two times independently with similar results. c, The gold standard Fourier shell correlation (FSC) curve of final density map. d, Angular distribution of particles included in the final 3D reconstruction. e, Cryo-EM density map of R1M2S1-DNARAS (44 bp) colored on the basis of the local resolution. f, Data-processing workflow for R2M2S1-DNA (44 bp).

Extended Data Fig. 4 Single particle cryo-EM analysis of R2M2S1 bound to 64bp DNA.

a, Representative cryo-EM micrograph of R2M2S1-DNA (64 bp). Experiments were performed two times independently with similar results. b, Representative reference-free 2D-class averages. Experiments were performed two times independently with similar results. c, The gold standard Fourier shell correlation (FSC) curve of final density map. d, Angular distribution of particles included in the final 3D reconstruction. e, Cryo-EM density map of R1M2S1-DNARAS (64 bp) colored on the basis of the local resolution. f, Data-processing workflow for R2M2S1-DNA (64 bp).

Extended Data Fig. 5 Single particle cryo-EM analysis of R2M2S1 bound to Ocr.

a,b, Representative cryo-EM micrographs of R2M2S1-Ocr (a) and R2M2S1-Ocr-Grafix (b). Experiments were performed two times independently with similar results. c,d, Representative reference-free 2D-class averages of R2M2S1-Ocr (c) and R2M2S1-Ocr-Grafix (d). Experiments were performed two times independently with similar results. e, Cryo-EM density maps of R1M2S1-OcrRAS-2-local colored on the basis of the local resolution. f,g, The gold standard Fourier shell correlation (FSC) curves of R2M2S1-Ocr (f) and R2M2S1-Ocr-Grafix (g). h, Angular distribution of particles included in the final 3D reconstruction of R1M2S1-OcrRAS-2-local. i,j, Data-processing workflows for R2M2S1-Ocr (i) and R2M2S1-Ocr-Grafix (j).

Extended Data Fig. 6 Single particle cryo-EM analysis of R2M2S1 bound to ArdA.

a,b, Representative cryo-EM micrographs of R2M2S1-ArdA (a) and R2M2S1-ArdA-Grafix (b). Experiments were performed two times independently with similar results. c,d, Representative reference-free 2D-class averages of R2M2S1-ArdA (c) and R2M2S1-ArdA-Grafix (d); Experiments were performed two times independently with similar results. e,f, Cryo-EM density maps of R1M2S1-ArdARAS (e) and R2M2S1-ArdATS-4 (f) colored on the basis of the local resolution. g, The gold standard Fourier shell correlation (FSC) curves of R2M2S1-ArdA complexes (upper panel); Corrected Fourier shell correlation (FSC) of R2M2S1-ArdATS-4 (blue solid line), FSC of the unmasked map (red dashed line), FSC of the masked map (green dashed line) and FSC of the randomized masked map (orange dashed line) (lower panel). h,i, Angular distribution of particles included in the final 3D reconstruction of R1M2S1-ArdARAS (h) and R2M2S1-ArdATS-4 (i). j,k, Data-processing workflows for R2M2S1-ArdA (j) and R2M2S1-ArdA-Grafix (k).

Extended Data Fig. 7 Representative cryo-EM density maps for different subunits/regions of EcoR124I complexes.

a, Cryo-EM density maps for DNA, Ocr, ArdA, and all the subunits of EcoR124I (HsdR, HsdM and HsdS). b, The representative maps for selected regions in the components of HsdR, ArdA, HsdM, and Ocr.

Extended Data Fig. 8 Structural features of M2S1 in closed form and R2M2S1 in translocation state.

a-c, Side view (upper panels) and top view (lower panels) of R2M2S1-DNATS (a), R2M2S1-OcrTS (b), and R2M2S1-ArdATS (c). Note that the two views are similar to that of Figs. 2a-2c. All the domains of HsdRs are color coded and labeled. HsdM, HsdS, Ocr, ArdA, and DNA have the same color codes as in Figs. 2a-2c. d, Top views of the two HsdM subunits in different structures. Note that the two HsdMs adopt an open conformation in both translocation and intermediate states. e, Structural superimposition between the two motor domains of HsdR in R2M2S1-DNATS and a DNA-translocating SWI2/SNF2 ATPase (PDB: 1Z63). f, Structural superimpositions between M2S1-DNA (colored in blue) and R2M2S1-DNATS (colored in green) using DNA (shown in cartoon and colored in gray) as the reference point. The catalytic pockets of HsdM subunits are shown in space-filling representation. The red arrows indicate the positions of the two adenines for methylation.

Extended Data Fig. 9 Structural features of intermediate state and critical roles of HsdR-CTD.

a,b, Side view (upper panels) and top view (lower panels) of R2M2S1-DNAIS (a) and R2M2S1-OcrIS (b). Note that the two views are similar to that of Figs. 3a and 3b. All the domains of HsdRs are color coded and labeled. HsdM, HsdS, Ocr, and DNA have the same color codes as in Figs. 3a and 3b. c, Structural superimposition between HsdRa of the intermediate state and HsdR of the translocation state. d, Secondary structure predictions of HsdR CTDs from representative members of different subtypes of Type I R-M systems. The grapy rectangles represent Helix structures. e-g, Elution profiles of SEC runs on Superdex 200 10/300 column and SDS-PAGE results of indicated fractions for EcoR124I (e), EcoKI (f), and StySBLI (g) systems. Black asterisks indicate the non-target proteins. Experiments were performed three times independently with similar results. Source data

Extended Data Fig. 10 Structural superimpositions between M2S1-DNA and R2M2S1-DNAIS and features of restriction-alleviation state.

a, Structural superimpositions between M2S1-DNA (colored in blue) and R2M2S1-DNAIS (colored in yellow) using DNA (shown in cartoon and colored in gray) as the reference point. The catalytic pockets of HsdM subunits are shown in space-filling representation. The red arrows indicate the positions of the two adenines for methylation. b-d, Side view (upper panels) and top view (lower panels) of R1M2S1-DNARAS (b), R1M2S1-OcrRAS (c), and R1M2S1-ArdARAS (d). Note that the two views are similar to that of Fig. 4a-c. All the domains of HsdRs are color coded and labeled. HsdM, HsdS, Ocr, ArdA, and DNA have the same color codes as in Fig. 4a-c.

Supplementary information

Supplementary Information

Supplementary Tables 1–3.

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Source Data Extended Data Fig. 1

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Source Data Extended Data Fig. 9

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Gao, Y., Cao, D., Zhu, J. et al. Structural insights into assembly, operation and inhibition of a type I restriction–modification system. Nat Microbiol (2020). https://doi.org/10.1038/s41564-020-0731-z

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