The NuA4 Core Complex Acetylates Nucleosomal Histone H4 through a Double Recognition Mechanism

Abstract

NuA4 catalyzes the acetylation of nucleosomes at histone H4, which is a well-established epigenetic event, controlling many genomic processes in Saccharomyces cerevisiae. Here we report the crystal structures of the NuA4 core complex and a cryoelectron microscopy structure with the nucleosome. The structures show that the histone-binding pocket of the enzyme is rearranged, suggesting its activation. The enzyme binds the histone tail mainly through the target lysine residue, with a preference for a small residue at the -1 position. The complex engages the nucleosome at the dish face and orients its catalytic pocket close to the H4 tail to achieve selective acetylation. The combined data reveal a space-sequence double recognition mechanism of the histone tails by a modifying enzyme in the context of the nucleosome.

Critical genomic regulation mediated by Enhancer of Polycomb

“…Most recently, the structure of the EPcA domain was solved in complex with the other piccolo-NuA4 subunits, and the first bypass mutant of EPL1 was identified using genetic suppression analysis that has been so powerful for the study of many critical proteins and biological processes (Hughes 2016; Prelich 1999; van Leeuwen et al 2017 ). These studies, building on earlier suppression of non-null alleles (Lin et al 2008), implicated Epl1 as being a critical Esa1 co-factor, and highlighted the importance of the physical Epl1-Esa1 interactions for acetyltransferase activity (Searle et al 2017; Xu et al 2016). …”

“…Building on earlier work, recent, mutagenesis- and structure-based studies in S. cerevisiae have assigned function to many residues of Epl1 (Searle et al 2017; Xu et al 2016), promoting a great expansion in understanding the importance of specific residues and their corresponding roles. Similar studies in other organisms might prove fruitful.…”

Cryo-electron microscopy of chromatin biology

“…Despite these advantages, identifying small NCP particles in vitreous ice can be challenging, and most cryo-EM NCP structures to date have been visualized with added mass, either from bulky post-transitional modifications (Wilson et al, 2016) or in complex with large protein assemblies (Maskell et al, 2015;Yamada et al, 2011;Xu et al, 2016). Chua and coworkers circumvented this problem by using a Volta phase plate, allowing increased contrast at low spatial frequencies and improved particle alignment (Chua et al, 2016).…”

“…(a) PFV intasome-NCP structure (EMD entry 2992; Maskell et al, 2015). (b) NuA4 acetylase-NCP structure (EMD entry 9536; Xu et al, 2016). (c) 53BP1-NCP-ubme structure (EMD entry 8246; Wilson et al, 2016).…”

Nuclear encoded photosynthesis genes are specifically controlled by the NuA4 complex

“…Transcription-Associated 1 (TRA1) recruit reader subunits and transcription factors, greatly improving specificity of the acetyltransferase subunit Essential SAS2-related Acetyltransferase 1 (ESA1) towards histones H4, H2A and H2A.Z in the chromatin context [13][14][15][16] . Molecular studies in yeast and animals support critical roles for the NuA4-dependent histone acetylation in DNArepair and transcription 17,18 .…”