Abstract
The NuA4/TIP60 acetyltransferase complex is required for gene regulation, DNA repair and cell cycle progression. The limited structural information impeded understanding of NuA4/TIP60 assembly and regulatory mechanism. Here, we report the 4.7 Å cryo-electron microscopy (cryo-EM) structure of a NuA4/TIP60 TEEAA assembly (Tra1, Eaf1, Eaf5, actin and Arp4) and the 7.6 Å cryo-EM structure of a TEEAA-piccolo assembly (Esa1, Epl1, Yng2 and Eaf6). The Tra1 and Eaf1 constitute the assembly scaffold. The Eaf1 SANT domain tightly binds to the LBE and FATC domains of Tra1 by ionic interactions. The actin/Arp4 peripherally associates with Eaf1 HSA domain. The Eaf5/7/3 (TINTIN) and piccolo modules largely pack against the FAT and HEAT repeats of Tra1 and their association depends on Eaf1 N-terminal and HSA regions, respectively. These structures elucidate the detailed architecture and molecular interactions between NuA4 subunits and offer exciting insights into the scaffolding and regulatory mechanisms of Tra1 pseudokinase.
Highlights
The NuA4/TIP60 acetyltransferase complex is required for gene regulation, DNA repair and cell cycle progression
The large size, lack of kinase activity, and presence in both NuA4 and SAGA complexes have suggested that Tra1/TRRAP may serve as a scaffold for complex assembly or for recruitment to chromatin[39,40], which offers a unique paradigm illuminating the non-catalytic functions of PIKKs
The previous electron microscopy (EM) studies suggested that both composition and conformation of the SAGA complexes show substantial heterogeneity[41,43]
Summary
The NuA4/TIP60 acetyltransferase complex is required for gene regulation, DNA repair and cell cycle progression. The Eaf5/7/3 (TINTIN) and piccolo modules largely pack against the FAT and HEAT repeats of Tra[1] and their association depends on Eaf[1] N-terminal and HSA regions, respectively These structures elucidate the detailed architecture and molecular interactions between NuA4 subunits and offer exciting insights into the scaffolding and regulatory mechanisms of Tra[1] pseudokinase. The large size, lack of kinase activity, and presence in both NuA4 and SAGA complexes have suggested that Tra1/TRRAP may serve as a scaffold for complex assembly or for recruitment to chromatin[39,40], which offers a unique paradigm illuminating the non-catalytic functions of PIKKs
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