233: Mechanistic basis of NuA3 recognition and H3K14 acetylation

️ Episode 233: Mechanistic basis of NuA3 recognition and H3K14 acetylation In this episode of PaperCast Base by Base, we explore Cryo-EM structures of the yeast NuA3 complex reveal how a cooperative Sas3–Nto1 binding cleft recognizes the H3 tail and directs acetylation of H3K14 Study Highlights:The authors report cryo-EM structures of NuA3 in apo, acetyl-CoA-bound, and acetyl-CoA plus H3 tail-bound states at ~3.7, 3.1, and 3.2 Å resolution respectively. The histone H3 tail binding cleft is formed cooperatively by the catalytic subunit Sas3 and the non-catalytic subunit Nto1, with a hydrophobic pocket engaging H3 residues 9–12 and a polar network contacting the backbone of residues 12–15, notably Gly13. Acetyl-CoA binding induces conformational changes in a histone-engaging loop and a CoA-engaging helix that expand the cleft and position catalytic residues Cys418 and Glu452 between H3K14 and the acetyl donor. Mutational and biochemical assays show L369R abolishes HAT activity, N354A partially reduces activity, and a G13R peptide is poorly acetylated, supporting the structural basis for H3K14 specificity and recruitment by H3K4me3/H3K36me3 readers. Conclusion:The structures define a cooperative Sas3–Nto1 recognition mechanism and Gly13-dependent substrate geometry that underlie NuA3 specificity for H3K14 acetylation Music:Enjoy the music based on this article at the end of the episode. Reference:Shi, W., Zhao, L., Wang, Y. et al. Mechanistic insights into histone recognition and H3K14 acetylation by the NuA3 histone acetyltransferase complex. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67049-0 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/nua3-h3k14-structure Episode Slug: nua3-h3k14-structure Keywords: NuA3, histone acetylation, H3K14, cryo-EM, Sas3-Nto1

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