Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, 261 Mountain View Drive, Colchester, Vermont 05446, United States.
Department of Biomedical and Health Sciences, University of Vermont, Burlington, Vermont 05405, United States.
J Med Chem. 2020 Nov 12;63(21):12799-12813. doi: 10.1021/acs.jmedchem.0c01178. Epub 2020 Oct 21.
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.
溴结构域表现出对核心和变体组蛋白蛋白上特定翻译后修饰模式的偏好。我们研究了 ATAD2B 溴结构域的配体特异性，并将其与其在 ATAD2 中的密切相关的同源物进行了比较。我们表明，ATAD2B 溴结构域识别组蛋白 H4 和 H2A 上的单乙酰化和二乙酰化赖氨酸修饰。我们使用结构-功能方法来鉴定乙酰赖氨酸结合口袋中的关键残基，这些残基决定了分子识别过程，并且我们研究了 ATAD2 溴结构域抑制剂与 ATAD2B 的结合。我们的分析表明，对于溴结构域抑制剂协调至关重要的接触在 ATAD2/B 溴结构域之间是保守的，许多残基在乙酰化赖氨酸识别中起双重作用。我们进一步表征了导致功能丧失的 ATAD2B 的另一种剪接变体。我们的结果概述了 ATAD2B 溴结构域的结构和功能特征，并确定了一种调节 ATAD2B 蛋白与染色质相互作用的新机制。
