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Structure of human chromatin-remodelling PBAF complex bound to a nucleosome

Nature volume 605, pages 166–171 (2022)Cite this article

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Abstract

DNA wraps around the histone octamer to form nucleosomes1, the repeating unit of chromatin, which create barriers for accessing genetic information. Snf2-like chromatin remodellers couple the energy of ATP binding and hydrolysis to reposition and recompose the nucleosome, and have vital roles in various chromatin-based transactions2,3. Here we report the cryo-electron microscopy structure of the 12-subunit human chromatin-remodelling polybromo-associated BRG1-associated factor (PBAF) complex bound to the nucleosome. The motor subunit SMARCA4 engages the nucleosome in the active conformation, which reveals clustering of multiple disease-associated mutations at the interfaces that are essential for chromatin-remodelling activity. SMARCA4 recognizes the H2A–H2B acidic pocket of the nucleosome through three arginine anchors of the Snf2 ATP coupling (SnAc) domain. PBAF shows notable functional modularity, and most of the auxiliary subunits are interwoven into three lobe-like submodules for nucleosome recognition. The PBAF-specific auxiliary subunit ARID2 acts as the structural core for assembly of the DNA-binding lobe, whereas PBRM1, PHF10 and BRD7 are collectively incorporated into the lobe for histone tail binding. Together, our findings provide mechanistic insights into nucleosome recognition by PBAF and a structural basis for understanding SMARCA4-related human diseases.

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Fig. 1: Overall structure of human PBAF bound to the nucleosome.
Fig. 2: Structure of the motor domain bound to the nucleosome in the active state.
Fig. 3: Structure of the SRM of the PBAF complex.
Fig. 4: Structures of the PBAF-specific subunits.

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Data availability

Coordinates and Cryo-EM density maps have been deposited in the Electron Microscopy Data Bank and Protein Data Bank under accession codes EMD-31926, 7VDV (PBAF–NCP complex); EMD-31925, 7VDT (the motor–NCP complex); EMD-31927 (NBL–DBL); and EMD-31928 (NBL–HBL). Source data are provided with this paper.

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Acknowledgements

We thank the Tsinghua University Branch of the China National Center for Protein Sciences (Beijing) for the cryo-EM facility. This work was supported by the National Key Research and Development Program (2019YFA0508902 to Z.C.), the National Natural Science Foundation of China (32130016 and 31825016 to Z.C.), Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, and Tsinghua-Peking Joint Center for Life Sciences.

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  1. These authors contributed equally: Junjie Yuan, Kangjing Chen

Authors and Affiliations

  1. MOE Key Laboratory of Protein Science, Tsinghua University, Beijing, China

    Junjie Yuan, Kangjing Chen, Wenbo Zhang & Zhucheng Chen

  2. School of Life Science, Tsinghua University, Beijing, China

    Junjie Yuan, Kangjing Chen, Wenbo Zhang & Zhucheng Chen

  3. Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing, China

    Junjie Yuan & Zhucheng Chen

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Contributions

J.Y. prepared the sample and performed the biochemical analysis. W.Z. did the initial tries. K.C. performed the EM analysis. Z.C. wrote the manuscript with help from all authors. Z.C. directed and supervised all of the research.

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Correspondence to Zhucheng Chen.

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Extended data figures and tables

Extended Data Fig. 1 CryoEM analysis of the PBAF-nucleosome complex.

(a) A representative negative staining micrograph from 20 micrographs. (b) A representative cryo-EM micrograph from 19,313 micrographs. (c) 2D class averages of characteristic projection views of cryo-EM particles. (The diameter of the circular mask: 32nm.). (d) Flowchart of the cryo-EM data processing. (e) Angular distributions of the cryo-EM particles in the final round of refinement. (f) Resolution estimation of the EM maps. Gold standard Fourier shell correlation (FSC) curves, showing the overall nominal resolutions of 3.4 Å, 2.8 Å, 3.2 Å, 3. 2 Å for the overall complex, motor-nucleosome region, the left part (NBL-DBL) and the right part (NBL-HBL) of the SRM, respectively. (g). Model-map FSC plot calculated by Phenix between the map and the model.

Extended Data Fig. 2 Local density maps of the PBAF-nucleosome complex.

(a) Local cryoEM maps of the motor module at a resolution of 2.8 Å. (b) Local cryoEM maps of the SRM at a resolution of 3.2 Å.

Extended Data Fig. 3 Inter-molecular interactions of the PBAF-nucleosome complex detected by CL-MS.

Subunits are colored as in Fig. 1. Cross-links supported by spatial proximity in the cryoEM structure are shown.

Extended Data Fig. 4 Exit DNA unwrapping and AD binding to NBL.

(a) Local cryoEM density of the nucleosomal DNA bound by the PBAF complex, superimposed with the DNA from the “601” nucleosome (colored grey, PDB code 3MVD)65. (b) Binding of the AD to PHF10 and SMARCB1 in the NBL. The circled region is enlarged in (c). (c) Binding of the AD to the CTL of PHF10. Multiple-sequence alignments of Arid2 proteins and human ARID1a around the binding interface. Conserved residues are highlighted in yellow. (d) Two views of the nucleosome together with the NBL, superimposed with the DNA from the “601” nucleosome (colored grey). The electrostatics of AD of ARID2 is calculated with Pymol.

Extended Data Fig. 5 Structural comparison of the motor domains bound to the nucleosome.

(a) Comparison of the motors of PBAF (colored as Fig. 2) and recombinant BAF (colored blue, PDB code 6ltj)19 bound to the nucleosome. The histone octamers are aligned. (b) Comparison of the motors of PBAF and endogenous BAF (colored pink, PBDDEV_00000056)18 bound to the nucleosome. The histone octamers are aligned. (c-d) Structural comparisons of the motor domains of PBAF (lobe 1 in green, lobe 2 in cyan), to the recombinant BAF (d, blue, PDB code 6ltj)19, endogenous BAF (e, colored pink, PBDDEV_00000056)18. The structures of lobe 1 are aligned. The boxed regions (the Brace helices and the ATPase pocket) are enlarged for further analysis at the bottom. (e) Comparison of the SMARCA4 motor of the PBAF complex and Snf2 motor bound to the nucleosome (colored yellow, PDB code 5Z3U)33. The histone octamers are aligned. (f) Structural comparisons of the motor domains of PBAF and Snf2 (colored yellow, PDB code 5Z3U). The structures of lobe 1 are aligned. The boxed regions are enlarged for further analyses in g and h.

Extended Data Fig. 6 Additional biochemical analyses.

(a) Representative SDS-PAGE gels of the WT and mutant PBAF complexes from 5 independent experiments. (b) Chromatin remodeling activity of WT and R1372A mutant at a substaturating concentration of enzyme. The nucleosome and the enzyme complex at 10 nM and 5 nM were used, respectively. Representative gel is shown on the top, and quantification of the remodeled product at the bottom. Data are presented as mean values +/− SD (n = 3 technical replicates). (c) Chromatin remodeling activities of different batch preparations of the WT and mutant PBAF complex. Nucleosomes at 10 nM, and the enzyme complex at the indicated concentrations were used. Representative gels are shown on the left, and quantification on the right. Data are presented as mean values +/− SD (n = 3 technical replicates).

Source data

Extended Data Fig. 7 Local structural analysis of PBAF.

(a) Structural comparison of the NBL of PBAF (color coded) and BAF (grey, PBD code 6ltj)19. SMARCB1 is aligned. (b) Nucleosome binding by the FH of PBAF (left), and BAF (right). (c) Structural comparison of the structural core of the HBL of PBAF (color coded) and BAF (grey). The structures of NTD of SMARCA4 are aligned. (d) Structural comparison of the helical bundle of PBAF (color coded) and BAF (grey). The structures of SMARCD1 are aligned. (e) Structural comparison of ARM of ARID2 (colored gold) and ARID1a (colored grey). The HSA helix is partially melted in PBAF, with Arg448 located at the loop region, whereas it is a part of the helix in BAF. (f) Structural comparison of the ARM domains of ARID2 (colored gold) and Rsc9 in RSC (colored grey, PDB code 6K15)25. (g) Structural comparison of DBL of PBAF (color coded) and RSC (grey) around A2BM region. The structures of A2BM and R6BD (Rsc6-binding domain) are aligned. (h) Structural comparison of the structural core of the HBL of PBAF (color coded) and RSC (grey). The structures of the SANT domain of SMARCC and Rsc8 are aligned.

Extended Data Fig. 8 Multiple sequence alignments of ARID2-like proteins.

The AD domain of human ARID1a is included. The conserved residues involved in binding to the PHF10 are highlighted in yellow.

Extended Data Fig. 9 Multiple sequence alignments of PHF10-like proteins.

The conserved residues of CTL involved in binding to the AD domain of ARID2 are highlighted in yellow.

Extended Data Fig. 10 Multiple sequence alignments of PBRM1-like proteins.

Only the sequences of the CTD are shown. The structures of the N-terminal BD, BAH and HMG domains are not resolved in current study, and not included in the alignments.

Extended Data Fig. 11 Structural comparison of PBAF, BAF and RSC bound to the nucleosome.

(a) Structural modularity of PBAF, with the motor, ARP and SRM modules highlighted in different colors. (b-c) Structural modularity of BAF (PDB code 6ltj)19 (b) and RSC (PDB code 6kw3)25 (c), and the comparison with PBAF shown on the right. The histone cores are aligned.

Extended Data Table 1 Cryo-EM data collection, refinement and validation statistics
Full size table
Extended Data Table 2 Components of the BAF and PBAF complexes
Full size table

Supplementary information

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This file contains raw data for Fig. 2f and Supplementary Fig. 6a–c.

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Yuan, J., Chen, K., Zhang, W. et al. Structure of human chromatin-remodelling PBAF complex bound to a nucleosome. Nature 605, 166–171 (2022). https://doi.org/10.1038/s41586-022-04658-5

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