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

Abstract

ATAD2 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.

Abo1 ATPase facilitates the dissociation of FACT from chromatin

“…We showed that Abo1 directly interacts with the N-terminal domain (NTD) of Spt16 using the FIN helix located at the N-terminal region (NTR). The NTR of Abo1 exhibits low sequence conservation among its homologues, suggesting that functional differences between Abo1 homologues may be linked to this N-terminal variability (27,29,30). The precise role of the NTR in Abo1’s function remains unclear, but it may serve as a domain for protein-protein interaction domain.…”

“…Abo1 has been identified as one of FACT's interaction partners (20)(21)(22)(23)(24)(25)(26). Abo1 is one of the histone chaperones that bind histone H3-H4 and regulates the chromatin dynamics (20,27).…”