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Structure of human TIP60-C histone exchange and acetyltransferase complex

Ben-Shem, Adam
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Nature ( 2024 ) Cite this article

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Abstract

Chromatin structure is a key regulator of DNA transcription, replication, and repair 1 . In humans, the TIP60/EP400 complex (TIP60-C) is a 20-subunit assembly that impacts chromatin structure via two enzymatic activities: ATP-dependent exchange of histone H2A/H2B for H2A.Z/H2B and histone acetylation, which in yeast are carried out by two independent complexes, SWR1 and NuA4, respectively 2,3 . How these activities are merged in humans into one super-complex and what this association entails for their structure, mechanism and recruitment to chromatin is unknown. Here we describe the 2.4-3.3 Å resolution structure of the endogenous human TIP60-C. We find a three lobed architecture composed of SWR1-like (SWR1L) and NuA4-like (NuA4L) parts, that associate with a TRRAP activator-binding module. The huge EP400 subunit harbors the ATPase motor, traverses twice the junction between SWR1L and NuA4L, and constitutes the scaffold of the three-lobed architecture. NuA4L is completely re-arranged compared to its yeast counterpart. TRRAP is flexibly tethered to NuA4L, in stark contrast to its robust connection to the complete opposite side of yeast NuA4 4-7 . A modeled nucleosome bound to SWR1L, supported by activity tests, suggests that some aspects of the histone exchange mechanism diverge from the yeast example 8,9 . Furthermore, a fixed actin module, as opposed to the mobile actin subcomplex in SWR1 8 , the flexibility of TRRAP and the weak effect of extra-nucleosomal DNA on exchange activity, lead to a different, activator-based, mode of enlisting TIP60-C to chromatin.

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Authors and Affiliations

  1. Université de Strasbourg, IGBMC UMR 7104 UMR S 1258, Illkirch, France

    Changqing Li, Ekaterina Smirnova, Charlotte Schnitzler, Corinne Crucifix, Arnaud Poterszman, Patrick Schultz, Gabor Papai & Adam Ben-Shem

  2. CNRS, UMR 7104, Illkirch, France

    Changqing Li, Ekaterina Smirnova, Charlotte Schnitzler, Corinne Crucifix, Arnaud Poterszman, Patrick Schultz, Gabor Papai & Adam Ben-Shem

  3. Inserm, UMR S 1258, Illkirch, France

    Changqing Li, Ekaterina Smirnova, Charlotte Schnitzler, Corinne Crucifix, Arnaud Poterszman, Patrick Schultz, Gabor Papai & Adam Ben-Shem

  4. Equipe labellisée Ligue Contre le Cancer, IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Changqing Li, Ekaterina Smirnova, Charlotte Schnitzler, Corinne Crucifix, Arnaud Poterszman, Patrick Schultz, Gabor Papai & Adam Ben-Shem

  5. Museum National d’Histoire Naturelle, U 1154 Inserm UMR 7196 CNRS, Paris, France

    Jean Paul Concordet & Alice Brion

Authors

  1. Changqing Li

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  2. Ekaterina Smirnova

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  3. Charlotte Schnitzler

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  4. Corinne Crucifix

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  5. Jean Paul Concordet

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  6. Alice Brion

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  7. Arnaud Poterszman

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  8. Patrick Schultz

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  9. Gabor Papai

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  10. Adam Ben-Shem

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Corresponding author

Correspondence to Adam Ben-Shem .

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Li, C., Smirnova, E., Schnitzler, C. et al. Structure of human TIP60-C histone exchange and acetyltransferase complex. Nature (2024). https://doi.org/10.1038/s41586-024-08011-w

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  • DOI : https://doi.org/10.1038/s41586-024-08011-w

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