Structural basis of nucleosome recognition by the human NuA4/TIP60 acetyltransferase complex

Abstract

The human Tat-interactive protein, 60 kilodalton (Tip60) histone acetyltransferase (HAT) complex (NuA4/TIP60 complex, from now on TIP60-C) is a central regulator of chromatin accessibility, coupling histone acetylation with transcriptional activation and genome stability. But how the catalytic HAT module engages its nucleosome substrate has remained unknown. Here we present the structure of the human TIP60-C HAT module bound to the nucleosome, revealing a defined binding architecture in which TIP60, EPC1, ING3, and MEAF6 cooperatively position the catalytic center on the nucleosome surface, with the HAT module anchored on the histone acidic patch and engaging the linker DNA. The structure uncovers an intramolecular interaction involving the N-terminal Tudor domain of the TIP60 acetyltransferase subunit that suggests a potential mechanism for autoregulation of HAT activity. Together, our findings define the core principles by which the human TIP60-C HAT module recognizes chromatin, establishing a structural foundation for understanding how TIP60-C modifies chromatin in metazoans.