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Structure of H3K36-methylated nucleosome–PWWP complex reveals multivalent cross-gyre binding

Nature Structural & Molecular Biology volume 27, pages 8–13 (2020)Cite this article

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Abstract

Recognition of histone-modified nucleosomes by specific reader domains underlies the regulation of chromatin-associated processes. Whereas structural studies revealed how reader domains bind modified histone peptides, it is unclear how reader domains interact with modified nucleosomes. Here, we report the cryo-electron microscopy structure of the PWWP reader domain of human transcriptional coactivator LEDGF in complex with an H3K36-methylated nucleosome at 3.2–Å resolution. The structure reveals multivalent binding of the reader domain to the methylated histone tail and to both gyres of nucleosomal DNA, explaining the known cooperative interactions. The observed cross-gyre binding may contribute to nucleosome integrity during transcription. The structure also explains how human PWWP domain-containing proteins are recruited to H3K36-methylated regions of the genome for transcription, histone acetylation and methylation, and for DNA methylation and repair.

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Fig. 1: Structure of the H3KC36me3-modified nucleosome bound to the PWWP domain of LEDGF.
Fig. 2: Nucleosome–PWWP interactions.
Fig. 3: Conserved mode of nucleosome–PWWP interaction.

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Data availability

Electron microscopy densities were deposited in the Electron Microscopy Data Bank with the accession code EMD-10069. The coordinate file for the LEDGF PWWP–165 bp H3KC36me3-modified nucleosome structure was deposited in the Protein Data Bank with the accession code 6S01.

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Acknowledgements

We thank C. Oberthür for help with LEDGF protein purification, U. Neef and S. Vos for maintaining insect cell stocks and S. Aibara for helpful discussion. H.W. was supported by an EMBO Long-Term Fellowship (grant no. ALTF 650-2017). P.C. was supported by the Deutsche Forschungsgemeinschaft (grant nos. SFB860, SPP1935, SPP2191), the Advanced Grant ‘TRANSREGULON’ from the European Research Council (grant agreement no. 693023) and the Volkswagen Foundation.

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  1. Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

    Haibo Wang, Lucas Farnung, Christian Dienemann & Patrick Cramer

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Contributions

H.W. and L.F. initiated the project. H.W. designed and conducted all of the experiments and data analysis unless stated otherwise. L.F. cloned and purified full-length LEDGF protein. C.D. maintained the EM facility and advised on microscope setup. P.C. supervised research. H.W. and P.C. wrote the manuscript with input from all authors.

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Correspondence to Patrick Cramer.

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Peer review information Anke Sparmann was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Binding of LEDGF to H3KC36me3-modified nucleosome.

a, EMSA reveals that full-length LEDGF preferentially binds to a H3KC36me3-modified nucleosome with longer (165 bp) DNA. Molar ratio of full-length LEDGF to indicated nucleosomes are shown on the top of each lane. Bands correspond to each component and complexes are labeled on the right. Bands of degraded LEDGF-bound nucleosomes are denoted with *. For gel source data, see Source Data Extended Data Fig. 1. b, Reconstructed EM density maps of 145bp and 165bp H3KC36me3-modified nucleosome with LEDGF. Note that the presence of the extra DNA in the latter complex leads to a defined additional density for the PWWP domain. c, Mass spectrometry measurement of the H3KC36me3 modified histone H3. Left: molecular weight measurement of H3K36C mutant. Right: molecular weight measurement of H3KC36me3 modified H3.

Source data

Extended Data Fig. 2 Cryo-EM data processing.

a, Data processing procedure for the complex of the 165 bp H3KC36me3-modified nucleosome with LEDGF using Warp and Relion. b, Fourier Shell Correlation (FSC) plot for the reconstruction using 55,142 particles in the indicated class (enclosed by dashed line in the final step in a). The overall resolution is 3.2 Å as determined by the FSC 0.143 criterion. c, Local resolution assessment of the final cryo-EM map. d, Euler angle distribution of particles used in the final 3D reconstruction.

Extended Data Fig. 3 Cryo-EM density.

a, A vertical slice through the structure. Models of all chains are shown as sticks and the cryo-EM density is shown as a gray mesh. b, A horizontal slice through the structure. Models of all chains are shown as sticks and the EM density is shown as a gray mesh. c, Density of histone H3 residue KC36me3 and its interacting residues of the aromatic cage in the PWWP domain. d, Density of DNA-interacting residues of patch 1. e, Density of part of the nucleosomal DNA at SHL 0. f, Density of the dyad DNA base pair. g, Density of the B-factor sharpened (left) and unsharpened (right) PWWP domain.

Extended Data Fig. 4 Nucleosome-PWWP interface and comparison with other PWWP-DNA structures.

a, Nucleosome-PWWP interface. Residues colored in white recognize H3KC36me3 and residues colored in green interact with DNA. b, Front and side view of DNA conformation comparison with other known PWWP-DNA structures. PDB code of the structures used are: 5XSK (HDGF) and 6IIS (HDGF3L, also known as HRP3). c, Schematic view of DNA interactions. Electrostatic interactions and hydrogen bonds are shown as yellow dashes. SHLs are denoted.

Extended Data Fig. 5 Comparison of the location of the PWWP domain in our nucleosome-PWWP complex structure with previously proposed models.

a, Front view of the comparison with two models proposed for LEDGF (gray) 25 or its highly conserved homolog HDGFL3 (yellow)26 with our structure (pink). Whereas in one model (yellow) the domain is rotated by around 180 degrees and shifted to SHL −1 on one DNA gyre, in another model (Gray) the domain is moved to SHL +6.5 and −1.5, and placed in the major groove of the DNA gyres. b, Side view of the comparison shown in panel a.

Extended Data Fig. 6 Comparison with other ‘royal’ family domains bound to methylated H3K36 peptides.

a, Structures of the PWWP, Tudor and chromo domain bound with methylated H3K36 peptides. PDB codes of structures used here are: 4HCZ (PHF1), 2F5K (MRG15) and 4PLI (H3K36me3 of MRG2). b, Superposition of all three structures shown in a. c, Placement of the PHF1 Tudor domain structure (yellow)60 onto our nucleosome-PWWP structure based on superposition of the H3 peptides in both structures reveals a clash between the Tudor domain and the nucleosomal DNA (red dashed circle). This shows that the Tudor domain must bind differently, and may unwind the end of nucleosomal DNA or alter the conformation of the H3 tail, or both.

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Wang, H., Farnung, L., Dienemann, C. et al. Structure of H3K36-methylated nucleosome–PWWP complex reveals multivalent cross-gyre binding. Nat Struct Mol Biol 27, 8–13 (2020). https://doi.org/10.1038/s41594-019-0345-4

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