The chromatin-remodelling complex SWI/SNF is highly conserved and has critical roles in various cellular processes, including transcription and DNA-damage repair1,2. It hydrolyses ATP to remodel chromatin structure by sliding and evicting histone octamers3,4,5,6,7,8, creating DNA regions that become accessible to other essential factors. However, our mechanistic understanding of the remodelling activity is hindered by the lack of a high-resolution structure of complexes from this family. Here we report the cryo-electron microscopy structure of Saccharomyces cerevisiae SWI/SNF bound to a nucleosome, at near-atomic resolution. In the structure, the actin-related protein (Arp) module is sandwiched between the ATPase and the rest of the complex, with the Snf2 helicase-SANT associated (HSA) domain connecting all modules. The body contains an assembly scaffold composed of conserved subunits Snf12 (also known as SMARCD or BAF60), Snf5 (also known as SMARCB1, BAF47 or INI1) and an asymmetric dimer of Swi3 (also known as SMARCC, BAF155 or BAF170). Another conserved subunit, Swi1 (also known as ARID1 or BAF250), resides in the core of SWI/SNF, acting as a molecular hub. We also observed interactions between Snf5 and the histones at the acidic patch, which could serve as an anchor during active DNA translocation. Our structure enables us to map and rationalize a subset of cancer-related mutations in the human SWI/SNF complex and to propose a model for how SWI/SNF recognizes and remodels the +1 nucleosome to generate nucleosome-depleted regions during gene activation9.
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Cryo-EM density maps have been deposited in the Electron Microscopy Data Bank under accession numbers EMD-20934 (complex with ADP-BeFx), EMD-20935 (complex with ATPγS), EMD-20933 (body). Model coordinates have been deposited in the Protein Data Bank under accession numbers 6UXW (complex with ADP-BeFx), 6UXV (body).
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We thank J. Remis for assistance with microscope operation and data collection and J. Pattie for computer support; A. Rosenzweig, I. Radhakrishnan and S. Fishbain for helpful discussion and comments on the manuscript; the staff at the Structural Biology Facility of Northwestern University for technical support. This work was supported by a Cornew Innovation Award from the Chemistry of Life Processes Institute at Northwestern University (to Y. He), a Catalyst Award by the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust (to Y. He), an Institutional Research Grant from the American Cancer Society (IRG-15-173-21 to Y. He), an H Foundation Core Facility Pilot Project Award (to Y. He). Y. He is supported by NIGMS grant R01GM135651, NCI grant P01CA092584 and a Pilot Project Award from NCI grant U54CA193419. Y. Han is a recipient of the Chicago Biomedical Consortium Postdoctoral Research Grant. A.A.R. is supported by the Molecular Biophysics Training Program from NIGMS/NIH (5T32 GM008382).
The authors declare no competing interests.
Peer review information Nature thanks Blaine Bartholomew 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 figures and tables
a, Coomassie-stained SDS–PAGE (4–12% gradient) showing the TAP-purified SWI/SNF complex from the yeast strain bearing a TAP tag at the C terminus of Snf2. SWI/SNF subunits are labelled on the basis of molecular weight. At least three purifications were performed with similar gel pattern. b, Schematic showing the assembly and purification protocol of the SWI/SNF–nucleosome complex before single particle cryo-EM analysis. SWI/SNF is first incubated with reconstituted nucleosome. The nucleosomal DNA contains a single-stranded overhang that is annealed to a biotinylated RNA molecule. Next, the assembled complex is immobilized onto streptavidin coated magnetic beads. Following washes, the complex is eluted using RNase H digestion. The eluted complex is then cross-linked and deposited onto an EM grid for vitrification. c, Domain organization of all subunits that has been built in the model from Fig. 1.b. Mammalian homologues are shown in parentheses. Newly built or homology regions are highlighted by red lines with residue numbers, whereas previous structures that were rigid-body docked in our map are indicated by black lines. Subunits are coloured as in Fig. 1. Abbreviations: QLQ, glutamine-leucine-glutamine; SnAC, Snf2 ATP coupling; AT, AT hook DNA-binding motif; SANT, SWI3, ADA2, N-CoR and TFIIIB′′ DNA-binding; ARID, AT-rich interaction domain.
a, A representative raw micrograph (out of 7,769 total images) of the SWI/SNF–nucleosome complex assembled in the presence of ADP-BeFx. b, Flow chart of the cryo-EM data-processing procedure. The particle stack of class 3 (198,543 particles; blue dashed box) after the first sorting was chosen for the combined processing (Extended Data Fig. 4). c, FSC curves of the complex showing a final average resolution of 8.96 Å (FSC = 0.143).
a, A representative raw micrograph (out of 6,903 total images) of the SWI/SNF–nucleosome complex assembled in the presence of ATPγS. b, Flow chart of the cryo-EM data-processing procedure. The particle stack of class 5 (192,029 particles; red dashed box) after the first sorting was chosen for the combined processing (Extended Data Fig. 4). c, FSC curves of the complex showing a final average resolution of 10 Å (FSC = 0.143).
With the exception of the INO80 complex, the ATPase modules of all these complexes bind to SHL +2 and SHL −2. INO80 engages the nucleosomal DNA at SHL −6 to −7. SWI/SNF is different from the INO80/SWR1 family remodellers in that its Arp module (Arp7/9) is sandwiched between the body and the ATPase modules. The Snf2 ATPase module is connected through the long HSA domain to the rest of the complex, whereas the ATPases INO80 and Swr1 directly contact the main body of the corresponding complexes. All remodellers are aligned based on histone proteins. The ATPase in each complex is coloured red, whereas Arp proteins are coloured green. PDB codes of the other chromatin remodellers are shown in parentheses.
a, The Swi3 coiled-coil dimer (left) resembles the structure of the dominant-negative allele of MYC (OmoMYC; PDB ID 5I4Z). The OmoMYC structure was rigid-body docked in the spine density corresponding to the Swi3 coiled-coil and then compared with the Swi3 coiled-coil. b, Swi3 forms an asymmetric dimer in the SWI/SNF complex. c, The density at the tip of the spine shows features of β-sheet and is therefore assigned to Snf12 based on closed proximity to Snf12 SWIB domain and secondary structure prediction.
a, The Snf5 RPT1 and Swi3 SWIRMA heterodimer was aligned with the human BAF47–BAF155 crystal structure (PDB ID 5GJK). b, The Snf5 RPT2 and Swi3 SWIRMB heterodimer was aligned with the human BAF47–BAF155 crystal structure (PDB ID 5GJK). c, The RPT1–SWIRMA interface shows slight differences with the RPT2–SWIRMB interface. RPT1 and RPT2 were aligned, resulting in the SWIRM domains slightly shifting from each other. d, Comparing the interfaces between the SWIRM domains and Swi1. The two SWIRM domains was aligned, resulting in Swi1 H4 (yellow; contacting SWIRMB) occupying a similar position as Swi1 H1 (gold) and Snf5 H-N on SWIRMA. In all panels, structural elements related to RPT1–SWIRMA are depicted with darker colours, whereas structures associated with RPT2–SWIRMB are shown in lighter colours.
a, The Swi1 ARM repeat domain is aligned with β-catenin (grey; PDB ID 3BCT). The insertions of the Swi1 ARM repeat domain are depicted in magenta. b, Detailed interaction between the Swi1 ARM repeat domain with the arm and hinge submodules. c, Detailed interaction between the Swi1 ARM repeat domain with the spine submodule. The EM density of Swi1 is also shown in b and c as mesh.
Extended Data Fig. 9 Interactions between the Snf2 anchor domain and the rest of the SWI/SNF complex.
a, The Snf2 anchor linker region interacts with the Swi1 ARM repeat domain. b, Snf2 anchor helices 1 and 2 are sandwiched between the two SANT domains of Swi3 in the hinge region. The EM density of Snf2 anchor is shown as mesh.
a, b, Snf6 (a) and Swp82 (b) are positioned at peripheral locations within SWI/SNF. Map and structural models are shown with Snf6 (a) and Swp82 (b) highlighted. Swp82 is in close proximity to the nucleosomal DNA near SHL −2 (b). c, The extranucleosomal DNA density is close to Snf6 and is indicated as dashed lines. The N termini of Swi1 and Snf5 are also labelled. The N-terminal regions of Swi1 and Snf5, which are highly flexible and therefore not resolved in the structure, could take trajectories close to the extranucleosomal DNA.
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Han, Y., Reyes, A.A., Malik, S. et al. Cryo-EM structure of SWI/SNF complex bound to a nucleosome. Nature 579, 452–455 (2020). https://doi.org/10.1038/s41586-020-2087-1
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