Patrick Schultz
IGBMC, UMR 7104 CNRS, U1258 INSERM, Université de Strasbourg
Changqing Li, Ekaterina Smirnova, Charlotte Schnitzler, Corinne Crucifix, Arnaud Poterszman, Patrick Schultz, Gabor Papaiand Adam Ben-Shem, in collaboration with Jean Paul Concordet (Museum National d’Histoire Naturelle, U 1154 Inserm, UMR 7196 CNRS)
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. We determined the 2.4 Å resolution cryo-EM 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 is exceptionally spread-out, 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 and establishes a novel interaction hub. TRRAP is flexibly tethered to this hub, in stark contrast to its robust connection to the complete opposite side of yeast NuA4. 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. The merging of two enzymatic complexes into one super-assembly leads to far reaching structural adaptations that alter their mechanism of action, target specificity, and recruitment to chromatin.
