Mechanism of chromatin remodelling revealed by the Snf2-nucleosome structure


Chromatin remodellers are helicase-like, ATP-dependent enzymes that alter chromatin structure and nucleosome positions to allow regulatory proteins access to DNA. Here we report the cryo-electron microscopy structure of chromatin remodeller Switch/sucrose non-fermentable (SWI2/SNF2) from Saccharomyces cerevisiae bound to the nucleosome. The structure shows that the two core domains of Snf2 are realigned upon nucleosome binding, suggesting activation of the enzyme. The core domains contact each other through two induced Brace helices, which are crucial for coupling ATP hydrolysis to chromatin remodelling. Snf2 binds to the phosphate backbones of one DNA gyre of the nucleosome mainly through its helicase motifs within the major domain cleft, suggesting a conserved mechanism of substrate engagement across different remodellers. Snf2 contacts the second DNA gyre via a positively charged surface, providing a mechanism to anchor the remodeller at a fixed position of the nucleosome. Snf2 locally deforms nucleosomal DNA at the site of binding, priming the substrate for the remodelling reaction. Together, these findings provide mechanistic insights into chromatin remodelling.

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Figure 1: Overall structure of Snf2 bound to the nucleosome around SHL2.
Figure 2: Structure of Snf2 in the nucleosome-bound state.
Figure 3: Binding of the nucleosomal DNA by Snf2.
Figure 4: Binding of nucleosomal DNA to the secondary DNA-binding sites of Snf2.
Figure 5: Directionality of DNA translocation driven by Snf2.
Figure 6: Model of nucleosome sliding by Snf2.


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We thank J. Lei at the Center for Structural Biology (Tsinghua University) and the staff at the Tsinghua University Branch of the National Center for Protein Sciences Beijing for providing facility support. This work was supported by the National Key Research and Development Program to Z.C. (2014CB910100) and to X.L (2016YFA0501102 and 2016YFA0501902), the National Natural Science Foundation of China to Z.C. (31570731, 31270762, 31630046) and to X.L. (31570730), Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, and the ‘Junior One Thousand Talents’ program to Z.C. and X.L.

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X.Liu and X.X. prepared the proteins and performed the biochemical analyses; M.L. collected the EM data with help from X.Liu and X.X.; M.L. and X.Li performed the EM analysis; Z.C. wrote the manuscript with help from all authors; Z.C. directed and supervised all the research.

Corresponding authors

Correspondence to Xueming Li or Zhucheng Chen.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks B. Bartholomew, T. Owen-Hughes 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 Negative-staining and cryo-EM structure analysis.

a, Representative micrograph of negative staining. b, Two-dimensional class averages of characteristic projection views of negative-staining particles. c, Negative-staining density map of SHL6 complex. d, Representative micrograph of cryo-EM sample. e, Fast Fourier transforms of image in d, with the Thon rings extending to ~3.5 Å. f, Two-dimensional class averages of characteristic projection views of cryo-EM particles of the Snf2–NCP complex. g, Angular distribution of particle projections of the SHL6 complex. h, Angular distribution of particle projections of the SHL2 complex. i, Cryo-EM density map of free NCP coloured on the basis of the local resolution and angular distribution of particle projections. j, Cryo-EM density map of the Snf2 part of the SHL6 complex coloured on the basis of the local resolution. k, Cryo-EM density map of the Snf2 part of the SHL2 complex coloured on the basis of the local resolution. l, The ‘gold-standard’ FSC curve calculated between two halves of data sets for the SHL6 complex, Snf2 (SHL6), the SHL2 complex, Snf2 (SHL2) and free nucleosome. m, Two-dimensional class averages of characteristic projection views of cryo-EM particles of the 2Snf2–NCP complex.

Extended Data Figure 2 Flow chart of cryo-EM data processing.

Inset: low-resolution models to show the linker DNA that helped to orient the complex. For the SHL6 complex, the model was acquired from the yellow class (14.8%); SHL2 complex, grey class (20.0%); 2Snf2–NCP complex, structure with two copies of Snf2 bound to the same NCP at SHL2 (pink) and SHL6 (red). Scale bar, 2 nm.

Extended Data Figure 3 Comparison of the structure of Snf2 bound at SHL2 and SHL6.

Snf2 bound at SHL2 is coloured as in Fig. 2, and that at SHL6 is coloured grey. Only the primary DNA is shown, with 5′- and 3′-strands bound by the Snf2 at SHL6 coloured magenta and orange, respectively. Red arrow indicates the proposed direction of DNA translocation driven by Snf2.

Extended Data Figure 4 Superposition of the structure and the EM density map.

a, Local resolution of the cryo-EM density map of the SHL2 complex. b, Segmented map of the nucleosome part of the SHL2 complex. c, Segmented map of ScSnf2. d, Region around W1185 of the SHL2 complex. Segmented maps of Snf2 and the 3′-DNA are coloured green and yellow, respectively. e, Region around R880 of the SHL6 complex.

Extended Data Figure 5 Conformational changes of Snf2 upon nucleosome binding.

The structure of core1 domains of MtSnf2 in the resting state (grey, PDB accession number 5HZR)7 was aligned with that of ScSnf2 (green) in complex with the NCP. For clarity, only the structure around the central β-sheets of the remodellers is shown. The core2 domains in the resting state and in the substrate state are coloured blue and cyan, respectively. The elements for ATP hydrolysis (motifs I and VI) are in red. Motif VI is disordered in the resting state, and becomes a helical structure in the nucleosome-bound state. The arrow indicates the movement of core2 domain relative to the core1 domain upon the binding of the nucleosome.

Extended Data Figure 6 Chromatin remodelling activities of various constructs used in this study.

a, Gels of the restriction enzyme-accessibility assays of ScSnf2 (666–1400) with wild-type interface and three core1–core2 interface mutants. The cut fractions were quantified and shown in Fig. 2g. Three independent assays were performed and one was shown. b, Gels of the restriction enzyme accessibility assays of three DNA-binding mutant ScSnf2 (666–1400). The cut fractions are shown in Fig. 3d. c, Gels of the restriction enzyme accessibility assays of three mutant ScSnf2 (666–1400) containing DNA-binding mutations in the secondary DNA-binding sites. The cut fractions were quantified and are shown in Fig. 4d. d, Gels of the restriction enzyme accessibility assays of ScSnf2 (666–1400) with wild-type interface towards gH4-NCP (left), H4-binding KK mutation of Snf2 towards intact NCP (middle) and KK mutant Snf2 towards gH4-NCP (right). The cut fractions were quantified and are shown in Extended Data Fig. 8f.

Extended Data Figure 7 Superposition of the structures of the core2 domains of ScSnf2 (cyan) and MtISWI (grey).

The Brace helices of ScSnf2 are shown in red; NegC of MtISWI (PBD code 5JXT)9 is in orange. V1235 of ScSnf2 is equivalent to V638 of MtISWI.

Extended Data Figure 8 Interactions between the histone H4 tail and ScSnf2.

a, Binding of the histone H4 tail to a highly negatively charged surface of ScSnf2. Electrostatic surface of ScSnf2 was calculated with Pymol. Red, negative electrostatic potential; blue, positive electrostatic potential. b, Superimposition of the structure of the ScSnf2–NCP complex, the EM density map around the H4 tail (filtered to a resolution of 7.0 Å, gold) and the crystal structure of the core2 domain of MtISWI (grey, PDB accession number 5JXT)9 in complex with the H4 tail (magenta). Acidic residues of MtISWI surrounding the H4-binding pocket are shown as sticks and labelled (grey), and the corresponding residues of ScSnf2 are also labelled (cyan). c, GST pull-down assays of ScSnf2 (666–1400) with intact interface and the H4-binding KK mutant. The experiments were repeated at least three times, and the representative gel shown. GST alone was used as a negative control. d, ATPase activities of ScSnf2 (666–1400) with wild-type interface (black) and KK mutation (red) in the resting state (-), and in the presence of DNA and NCP. e, GST pull-down assays of ScSnf2 (666–1400) with wild-type and four mutant H4 tail peptides. f, Chromatin remodelling activities of ScSnf2 (666–1400) with wild-type interface (black) and KK mutation (red) towards intact (filled symbols) and mutant gH4 (open symbols) NCPs. For gel source data, see Supplementary Fig. 1.

Extended Data Figure 9 Superposition of the structures of ScSnf2 and SsoRad54 (grey).

The structures of the core1 domains of ScSnf2 and SsoRad54 (PDB accession number 1Z63)26 are aligned. The DNA bound by SsoRad54 is coloured light blue. The six DNA-binding elements of ScSnf2 (motifs Ia, Ib, II, IV, V and core2i) are labelled and coloured blue. Motifs IV and V of SsoRad54 are coloured magenta.

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Liu, X., Li, M., Xia, X. et al. Mechanism of chromatin remodelling revealed by the Snf2-nucleosome structure. Nature 544, 440–445 (2017).

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