Crystal structure of yeast Esa1 suggests a unified mechanism for catalysisand substrate binding by histone acetyltransferases

Esa1 is the catalytic subunit of the NuA4 histone acetylase (HAT) complex t hat acetylates histone H4, and it is a member of the MYST family of HAT pro teins that includes the MOZ oncoprotein and the HIV-1 Tat interacting prote in Tip60. Here we report the X-ray crystal structure of the HAT domain of E sa1 bound to coenzyme A and investigate the protein's catalytic mechanism. Our data reveal that Esa1 contains a central core domain harboring a putati ve catalytic base, and flanking domains that are implicated in histone bind ing. Comparisons with the Gcn5/PCAF and Hat1 proteins suggest a unified mec hanism of catalysis and histone binding by HAT proteins, whereby a structur ally conserved core domain mediates catalysis, and sequence variability wit hin a structurally related N- and C-terminal scaffold determines substrate specificity.