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Epigenetic mechanism

Paralog-specific recognition

Nature Chemical Biology volume 19, pages 542–543 (2023)Cite this article

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Substrate–inhibitor conjugation facilitates structural determination of the KDM2A/B-nucleosome complexes, which provides mechanistic insights into the nucleosomal H3K36 demethylation by KDM2A/B and reveals a paralog-specific nucleosome acidic patch recognition mechanism mediated by the N terminus of KDM2A but not KDM2B.

The dynamic and reversible histone post-translational modifications (PTMs) play essential roles in the regulation of all the chromatin-associated processes. These chromatin PTMs (or ‘markers’) create a complex epigenetic landscape, whose precise regulation is critical to the establishment and maintenance of cell identity1. Histone methylation engages in versatile nuclear processes, and is regulated by the histone lysine demethylases (KDMs)2. Structures of KDMs in complex with their substrates provide insights into the mechanism that underlies its sequence-specific demethylase activity3. In this issue of Nature Chemical Biology, Spangler, Skrajna et al.4 reported cryo-electron microscopy (cryo-EM) structures of KDM2A/B in complex with the nucleosomes and revealed that KDM2-mediated nucleosomal histone H3 lysine 36 (H3K36) demethylation is facilitated by the histone charge shielding and dynamic nucleosomal DNA unwrapping, and KDM2A/B-nucleosome binding is paralog-specific, of which only KDM2A, but not KDM2B, binds to the H2A–H2B acidic patch through its N terminus.

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Fig. 1: Chemical trapping strategy enables the cryo-EM determination of KDM2A/B bound to nucleosome.

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Authors and Affiliations

  1. Tsinghua-Peking Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China

    Huasong Ai & Lei Liu

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  1. Huasong Ai
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  2. Lei Liu
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Correspondence to Lei Liu.

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The authors declare no competing interests.

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Ai, H., Liu, L. Paralog-specific recognition. Nat Chem Biol 19, 542–543 (2023). https://doi.org/10.1038/s41589-022-01241-x

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  • DOI: https://doi.org/10.1038/s41589-022-01241-x

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