Structural Insights into the Recognition of Mono- and Diacetylated Histones by the ATAD2B Bromodomain

Bromodomains exhibit preferences
for specific patterns of post-translational
modifications on core and variant histone proteins. We examined the
ligand specificity of the ATAD2B bromodomain and compared it to its
closely related paralogue in ATAD2. We show that the ATAD2B bromodomain
recognizes mono- and diacetyllysine modifications on histones H4 and
H2A. A structure–function approach was used to identify key
residues in the acetyllysine-binding pocket that dictate the molecular
recognition process, and we examined the binding of an ATAD2 bromodomain
inhibitor by ATAD2B. Our analysis demonstrated that critical contacts
required for bromodomain inhibitor coordination are conserved between
the ATAD2/B bromodomains, with many residues playing a dual role in
acetyllysine recognition. We further characterized an alternative
splice variant of ATAD2B that results in a loss of function. Our results
outline the structural and functional features of the ATAD2B bromodomain
and identify a novel mechanism regulating the interaction of the ATAD2B
protein with chromatin.