8QRI

TRRAP and EP400 in the human Tip60 complex

Summary for 8QRI

• Entry DOI: 10.2210/pdb8qri/pdb
• EMDB information: 18619
• Descriptor: Transformation/transcription domain-associated protein, E1A-binding protein p400 (2 entities in total)
• Functional Keywords: eukaryotic transcription, histone acetyltransferase, chromatin remodeling, complex, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 782006.84

Authors

Li, C.,Smirnova, E.,Schnitzler, C.,Crucifix, C.,Concordet, J.P.,Brion, A.,Poterszman, A.,SChultz, P.,Papai, G.,Ben-Shem, A. (deposition date: 2023-10-09, release date: 2024-08-07, Last modification date: 2024-12-04)

Primary citation

Li, C.,Smirnova, E.,Schnitzler, C.,Crucifix, C.,Concordet, J.P.,Brion, A.,Poterszman, A.,Schultz, P.,Papai, G.,Ben-Shem, A.
Structure of the human TIP60-C histone exchange and acetyltransferase complex.
Nature, 635:764-769, 2024

PubMed Abstract: Chromatin structure is a key regulator of DNA transcription, replication, and repair. 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. 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. A modeled nucleosome bound to SWR1L, supported by activity tests, suggests that some aspects of the histone exchange mechanism diverge from the yeast example. Furthermore, a fixed actin module, as opposed to the mobile actin subcomplex in SWR1, 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.

PubMed: 39260417
DOI: 10.1038/s41586-024-08011-w

Experimental method

ELECTRON MICROSCOPY (3.5 Å)