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Structure of the variant histone H3.3–H4 heterodimer in complex with its chaperone DAXX

Nature Structural & Molecular Biology volume 19, pages 1287–1292 (2012)Cite this article

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Abstract

Mammalian histone H3.3 is a variant of the canonical H3.1 essential for genome reprogramming in fertilized eggs and maintenance of chromatin structure in neuronal cells. An H3.3-specific histone chaperone, DAXX, directs the deposition of H3.3 onto pericentric and telomeric heterochromatin. H3.3 differs from H3.1 by only five amino acids, yet DAXX can distinguish the two with high precision. By a combination of structural, biochemical and cell-based targeting analyses, we show that Ala87 and Gly90 are the principal determinants of human H3.3 specificity. DAXX uses a shallow hydrophobic pocket to accommodate the small hydrophobic Ala87 of H3.3, whereas a polar binding environment in DAXX prefers Gly90 in H3.3 over the hydrophobic Met90 in H3.1. An H3.3–H4 heterodimer is bound by the histone-binding domain of DAXX, which makes extensive contacts with both H3.3 and H4.

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Figure 1: Overall structure of the DAXX HBD–H3.3–H4 complex.
Figure 2: Conformational differences between the DAXX HBD–bound and nucleosomal H3.3–H4 complexes.
Figure 3: H3.3 residues responsible for DAXX binding specificity.
Figure 4: DAXX residues important for recognition of H3.3.

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Acknowledgements

We thank SSRF beamline scientists for technical support during data collection. The work was supported by grants from the Chinese Ministry of Science and Technology (2009CB825501 to R.-M.X. and 2011CB966300 to G.L.), the Natural Science Foundation of China (31210103914, 90919029 and 3098801 to R.-M.X. and 31071147 to G.L.) and the Chinese Academy of Sciences Strategic Priority Research Program (XDA01010304 to G.L.). R.-M.X. is a CAS-Novo Nordisk Great Wall Professor.

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  1. Chao-Pei Liu and Chaoyang Xiong: These authors contributed equally to this work.

Authors and Affiliations

  1. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Chao-Pei Liu, Chaoyang Xiong, Mingzhu Wang, Zhouliang Yu, Na Yang, Ping Chen, Guohong Li & Rui-Ming Xu

  2. University of Chinese Academy of Sciences, Beijing, China

    Zhouliang Yu

  3. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA

    Zhiguo Zhang

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  1. Chao-Pei Liu
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Contributions

R.-M.X., G.L. and Z.Z. conceived of the project, R.-M.X. and G.L. designed the experiments and Z.Z. contributed reagents. C.-P.L, C.X., M.W., Z.Y., N.Y. and P.C. performed the experiments, and all authors analyzed the data. C.-P.L., G.L. and R.M.X. wrote the paper.

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Correspondence to Guohong Li or Rui-Ming Xu.

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Liu, CP., Xiong, C., Wang, M. et al. Structure of the variant histone H3.3–H4 heterodimer in complex with its chaperone DAXX. Nat Struct Mol Biol 19, 1287–1292 (2012). https://doi.org/10.1038/nsmb.2439

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