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Structure of the NuA4 acetyltransferase complex bound to the nucleosome

Abstract

Deoxyribonucleic acid in eukaryotes wraps around the histone octamer to form nucleosomes1, the fundamental unit of chromatin. The N termini of histone H4 interact with nearby nucleosomes and play an important role in the formation of high-order chromatin structure and heterochromatin silencing2,3,4. NuA4 in yeast and its homologue Tip60 complex in mammalian cells are the key enzymes that catalyse H4 acetylation, which in turn regulates chromatin packaging and function in transcription activation and DNA repair5,6,7,8,9,10. Here we report the cryo-electron microscopy structure of NuA4 from Saccharomyces cerevisiae bound to the nucleosome. NuA4 comprises two major modules: the catalytic histone acetyltransferase (HAT) module and the transcription activator-binding (TRA) module. The nucleosome is mainly bound by the HAT module and is positioned close to a polybasic surface of the TRA module, which is important for the optimal activity of NuA4. The nucleosomal linker DNA carrying the upstream activation sequence is oriented towards the conserved, transcription activator-binding surface of the Tra1 subunit, which suggests a potential mechanism of NuA4 to act as a transcription co-activator. The HAT module recognizes the disk face of the nucleosome through the H2A–H2B acidic patch and nucleosomal DNA, projecting the catalytic pocket of Esa1 to the N-terminal tail of H4 and supporting its function in selective acetylation of H4. Together, our findings illustrate how NuA4 is assembled and provide mechanistic insights into nucleosome recognition and transcription co-activation by a HAT.

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Fig. 1: Overall structure of the NuA4 complex bound to the nucleosome.
Fig. 2: Structure of the TRA module.
Fig. 3: Structure of the HAT module bound to the nucleosome.

Data availability

Coordinates and EM maps are deposited in the Protein Data Bank under accession codes EMD-32149, PDB ID 7VVY (TRA module), EMD-32148, PDB ID 7VVU (NCP-HAT), EMD-32150, PDB ID 7VVZ (NuA4–NCP), EMD-32156 (ARP submodule) and EMD-32157 (Tra1 Head).

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Acknowledgements

We thank S.-C. Cheng (Institute of Molecular Biology, Academia Sinica) for providing yeast strain BJ2168 and the Tsinghua University Branch of the China National Center for Protein Sciences (Beijing) for use of the cryo-EM facility. This work was supported by the National Key Research and Development Program (no. 2019YFA0508902 to Z.C), the National Natural Science Foundation of China (nos. 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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Contributions

K.Q. prepared samples and performed biochemical analysis. K.Q. and K.C. built the atomic model. K.C., K.Q., H.W. and X.L. performed EM analysis. Z.C. wrote the manuscript with help from all authors. Z.C. directed and supervised all of the research.

Corresponding authors

Correspondence to Xueming Li or Zhucheng Chen.

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The authors declare no competing interests.

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Extended data figures and tables

Extended Data Fig. 1 Biochemistry of NuA4 and the crosslinking data detected by CL-MS.

(a) Preparation of endogenous NuA4 complex from S.cerevisiae. SDS-PAGE gels were showed with Coomassie stain. More sample of the WT complex was loaded to show the weak bands on the right panel. Over 10 batches of the samples were prepared, and the representative two are shown here. (b) Relative HAT activity of NuA4 towards the nucleosomes in the absence and presence of Gal4-VP16. The Gal4 binding site (UAS) was placed at different positions of the nucleosomes (UAS-0N20, UAS-10N20 and UAS-20N20), and the unrelated sequence was used as a control (con-20N20). Acetylation of H4 was detected by Western blotting. A presentative gel was shown on the top, and quantification at the bottom. The activities were normalized to the ones in the absence of Gal4-VP16. Two technical replicates were performed. (c) Overview of the cross-linking data. Circular plot of high confidence lysine-lysine inter-subunit crosslinks obtained by mass spectrometry for the NuA4-NCP complex. (d) Validated cross-links mapped onto the NuA4-NCP structure. Blue lines, the intra-chain cross-links with cross-linked sites within the 30 Å distance permitted by BS3; green lines, the inter-chain cross-links, whereas red lines depict cross-link over more than 30 Å. Bottom graph displays the distribution of cross-link distances. A vertical line indicates a cutoff at 30 Å, the distance considered reasonable for BS3 crosslinks. (e) Relative HAT activity of an independent batch of WT and DM mutant NuA4 different from that of Fig. 2f. Four technical replicates were performed.

Source Data

Extended Data Fig. 2 Cryo-EM analysis of the NuA4-NCP complex in the absence and presence of Gal4-VP16.

(a) Representative negative stain images (top panel), cryo-EM images (middle panel), and 2D classification (bottom panel) of NuA4+NCP. (b) Flowcharts of the cryo-EM data processing for the dataset of NuA4+NCP. (c) Representative negative stain images (top panel), cryo-EM images (middle panel), and 2D classification (bottom panel) of NuA4+NCP+Gal4-VP16. (d) Flowcharts of the cryo-EM data processing for the dataset of NuA4+NCP+Gal4-VP16.

Extended Data Fig. 3 Chemistry and Mass-spectrometry analyses of the modified histones.

(a) Schematic diagram of the chemical semi-synthesis of histone H4 with CMC modification at Lys16. (b) Mass-spectrometry identification of the CMC-modified H4 (the expected mass is 11092.57 Da). (c) Mass-spectrometry identification of the H3KC36me3-modified H3 (the expected mass is 15299.76 Da).

Extended Data Fig. 4 Cryo-EM analysis of the NuA4-NCP complex in the presence of Gal4-VP16 and histone-modified nucleosome.

(a) Representative negative stain images (left panel), cryo-EM images (middle panel), and 2D classification (right panel) of NuA4+Gal4-VP16 bound to the H4- and H3-modified nucleosome. (b) Flowcharts of the cryo-EM data processing for the dataset of NuA4+Gal4-VP16 bound to the H4- and H3-modified nucleosome. (c-d) Angular distributions of cryo-EM particles in the final round of refinement of the masked dataset and the estimation of the local resolutions of the TRA module (c) and the nucleosome bound HAT module (d). (e) Gold standard Fourier shell correlation (FSC) curves, showing the overall nominal resolutions of 6.7 Å, 3.4 Å, 3.1 Å, 2.8 Å, 2.7 Å and 2.7 Å for the NCP-HAT with longer linker DNA, the nucleosome bound HAT module, TRA module, the NCP bound with arginine anchors (RAs), ARP submodule, head of Tra1 bound with Eaf1/Eaf2/Epl1, respectively.

Extended Data Fig. 5 Local density maps of the NuA4-nucleosome complex.

(a) Local cryo-EM maps of the TRA module. PBL, polybasic loop. (b) Local cryo-EM maps of the HAT module bound to the nucleosome. EM densities of four consecutive base pairs at the central position of the nucleosome are showed on the left.

Extended Data Fig. 6 Multiple sequence alignments of Eaf2-like proteins.

The conserved residues are indicated by “*”. The secondary structural assignments are based on the structure of Eaf2.

Extended Data Fig. 7 Multiple sequence alignments of Epl1-like proteins.

The conserved residues are indicated by “*”. The secondary structural assignments are based on the structure of Epl1.

Extended Data Fig. 8 Multiple sequence alignments of Eaf1-like proteins.

The conserved residues are indicated by “*”. The secondary structural assignments are based on the structure of Eaf1.

Extended Data Fig. 9 Additional structural analysis of the HAT module.

(a) Comparison of the structures of the HAT module bound to the nucleosome (color coded) and the nucleosome-free Piccolo subcomplex (colored grey, PBD code 5J9W)15. The structure of the Esa1 subunit is aligned. (b) Structural alignment of CMC-binding pocket in NuA4 (color coded) and in Esa1 (colored grey, PBD code 3TO6)21. (c) Structural comparison of CMC-binding in NuA4 (color coded) and AcCoA in Piccolo (colored grey, PBD code 5J9W)15.

Extended Data Table 1 Cryo-EM data collection, refinement and validation statistics

Supplementary information

Supplementary Fig. 1

Uncropped gels.

Reporting Summary

Supplementary Table 1

Data of CL–MS.

Supplementary Video 1

Cryo-EM density and model fitting of NuA4 bound to the nucleosome.

Supplementary Video 2

Multi-body refinement analysis of the NuA4–nucleosome complex.

Source data

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Qu, K., Chen, K., Wang, H. et al. Structure of the NuA4 acetyltransferase complex bound to the nucleosome. Nature 610, 569–574 (2022). https://doi.org/10.1038/s41586-022-05303-x

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