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

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. [Display omitted] •Esa1 within the NuA4 core complex is activated through interactions with Epl1•Esa1 recognizes the histone tail through a GK/AK motif•The NuA4 core complex binds the nucleosome, presenting the H4 tail to the active site•The NuA4 core complex targets the nucleosomal H4 tail by a double recognition mode Xu et al. report the crystal structure of the NuA4 core complex, a key histone acetyltransferase complex in yeast, and the cryo-EM structure bound with the nucleosome. Their structural and biochemical analyses show that the enzyme complex selectively acetylates the nucleosomal H4 tail through a space-sequence double recognition mechanism.