2 research outputs found
Coordination of di-acetylated histone ligands by the ATAD2 bromodomain
Open access article. Creative Commons Attribution 4.0 International license (CC BY 4.0) appliesThe ATPase Family, AAA domain-containing protein 2 (ATAD2) bromodomain (BRD)
has a canonical bromodomain structure consisting of four -helices. ATAD2 functions as a coactivator
of the androgen and estrogen receptors as well as the MYC and E2F transcription factors.
ATAD2 also functions during DNA replication, recognizing newly synthesized histones. In addition,
ATAD2 is shown to be up-regulated in multiple forms of cancer including breast, lung, gastric,
endometrial, renal, and prostate. Furthermore, up-regulation of ATAD2 is strongly correlated with
poor prognosis in many types of cancer, making the ATAD2 bromodomain an innovative target for
cancer therapeutics. In this study, we describe the recognition of histone acetyllysine modifications by
the ATAD2 bromodomain. Residue-specific information on the complex formed between the histone
tail and the ATAD2 bromodomain, obtained through nuclear magnetic resonance spectroscopy (NMR)
and X-ray crystallography, illustrates key residues lining the binding pocket, which are involved
in coordination of di-acetylated histone tails. Analytical ultracentrifugation, NMR relaxation data,
and isothermal titration calorimetry further confirm the monomeric state of the functionally active
ATAD2 bromodomain in complex with di-acetylated histone ligands. Overall, we describe histone
tail recognition by ATAD2 BRD and illustrate that one acetyllysine group is primarily engaged by the
conserved asparagine (N1064), the “RVF” shelf residues, and the flexible ZA loop. Coordination of a
second acetyllysine group also occurs within the same binding pocket but is essentially governed by
unique hydrophobic and electrostatic interactions making the di-acetyllysine histone coordination
more specific than previously presumed.Ye
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Structural insights into acetylated histone ligand recognition by the BDP1 bromodomain of Plasmodium falciparum
Plasmodium falciparum requires a two-host system, moving between Anopheles mosquito and humans, to complete its life cycle. To overcome such dynamic growth conditions its histones undergo various post-translational modifications to regulate gene expression. The P. falciparum Bromodomain Protein 1 (PfBDP1) has been shown to interact with acetylated lysine modifications on histone H3 to regulate the expression of invasion-related genes. Here, we investigated the ability of the PfBDP1 bromodomain to interact with acetyllsyine modifications on additional core and variant histones. A crystal structure of the PfBDP1 bromodomain (PfBDP1-BRD) reveals it contains the conserved bromodomain fold, but our comparative analysis between the PfBDP1-BRD and human bromodomain families indicates it has a unique binding mechanism. Solution NMR spectroscopy and ITC binding assays carried out with acetylated histone ligands demonstrate that it preferentially recognizes tetra-acetylated histone H4, and we detected weaker interactions with multi-acetylated H2A.Z in addition to the previously reported interactions with acetylated histone H3. Our findings indicate PfBDP1 may play additional roles in the P. falciparum life cycle, and the distinctive features of its bromodomain binding pocket could be leveraged for the development of new therapeutic agents to help overcome the continuously evolving resistance of P. falciparum against currently available drugs