Structure of the Human ATAD2 AAA+ Histone Chaperone Reveals Mechanism of Regulation and Inter-subunit Communication

Abstract

ABSTRACTATAD2 is a non-canonical ATP-dependent histone chaperone and a major cancer. Despite widespread efforts to design drugs targeting the ATAD2 bromodomain, little is known about the overall structural organization and AAA+ domains of ATAD2. Here, we present the 3.1 Å cryo-EM structure of human ATAD2 in the ATP state, showing a shallow hexameric spiral that binds a peptide substrate at the central pore. The spiral conformation is locked by an N-terminal linker domain (LD) that wedges between the seam subunits, thus limiting ATP-dependent symmetry breaking of the AAA+ ring. In contrast, a structure of the ATAD2-histone H3H4 complex shows the LD undocked from the seam, suggesting that H3H4 binding unlocks the AAA+ spiral by allosterically releasing the LD. These findings, together with the discovery of an inter-subunit signaling mechanism, reveal a unique regulatory mechanism for ATAD2 and lay the foundation for developing new ATAD2 inhibitors.