Structure of the human TIP60-C histone exchange and acetyltransferase complex

Nature. 2024 Nov;635(8039):764-769. doi: 10.1038/s41586-024-08011-w. Epub 2024 Sep 11.

Abstract

Chromatin structure is a key regulator of DNA transcription, replication and repair1. In humans, the TIP60-EP400 complex (TIP60-C) is a 20-subunit assembly that affects chromatin structure through two enzymatic activities: ATP-dependent exchange of histone H2A-H2B for H2A.Z-H2B, and histone acetylation. In yeast, however, these activities are performed by two independent complexes-SWR1 and NuA4, respectively2,3. How the activities of the two complexes are merged into one supercomplex in humans, and what this association entails for the structure and mechanism of the proteins and their recruitment to chromatin, are unknown. Here we describe the structure of the endogenous human TIP60-C. We find a three-lobed architecture composed of SWR1-like (SWR1L) and NuA4-like (NuA4L) parts, which associate with a TRRAP activator-binding module. The huge EP400 subunit contains the ATPase motor, traverses the junction between SWR1L and NuA4L twice and constitutes the scaffold of the three-lobed architecture. NuA4L is completely rearranged compared with its yeast counterpart. TRRAP is flexibly tethered to NuA4L-in stark contrast to its robust connection to the completely opposite side of NuA4 in yeast4-7. A modelled nucleosome bound to SWR1L, supported by tests of TIP60-C activity, suggests that some aspects of the histone exchange mechanism diverge from what is seen in yeast8,9. Furthermore, a fixed actin module (as opposed to the mobile actin subcomplex in SWR1; ref. 8), the flexibility of TRRAP and the weak effect of extranucleosomal DNA on exchange activity lead to a different, activator-based mode of enlisting TIP60-C to chromatin.

MeSH terms

  • Acetylation
  • Actins / chemistry
  • Actins / metabolism
  • Actins / ultrastructure
  • Adaptor Proteins, Signal Transducing* / chemistry
  • Adaptor Proteins, Signal Transducing* / metabolism
  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphatases / metabolism
  • Chromatin / chemistry
  • Chromatin / metabolism
  • Chromatin / ultrastructure
  • Cryoelectron Microscopy
  • DNA / chemistry
  • DNA / metabolism
  • DNA Helicases* / chemistry
  • DNA Helicases* / metabolism
  • DNA Helicases* / ultrastructure
  • DNA-Binding Proteins* / chemistry
  • DNA-Binding Proteins* / metabolism
  • DNA-Binding Proteins* / ultrastructure
  • Histone Acetyltransferases* / chemistry
  • Histone Acetyltransferases* / metabolism
  • Histone Acetyltransferases* / ultrastructure
  • Histones* / chemistry
  • Histones* / metabolism
  • Histones* / ultrastructure
  • Humans
  • Lysine Acetyltransferase 5* / chemistry
  • Lysine Acetyltransferase 5* / metabolism
  • Lysine Acetyltransferase 5* / ultrastructure
  • Models, Molecular
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Multiprotein Complexes / ultrastructure
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / ultrastructure
  • Nucleosomes / chemistry
  • Nucleosomes / metabolism
  • Nucleosomes / ultrastructure
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Adenosine Triphosphatases
  • Chromatin
  • DNA-Binding Proteins
  • EP400 protein, human
  • Histone Acetyltransferases
  • Histones
  • KAT5 protein, human
  • Lysine Acetyltransferase 5
  • Multiprotein Complexes
  • Nucleosomes
  • Protein Subunits
  • transformation-transcription domain-associated protein
  • DNA Helicases
  • Nuclear Proteins
  • NuA4 protein, S cerevisiae
  • Actins
  • DNA