The ATPase family AAA⁺ domain containing 2 (ATAD2) protein and its paralog ATAD2B have a C-terminal bromodomain (BRD) that functions as a reader of acetylated lysine residues on histone proteins. Using a structure–function approach, we investigated the ability of the ATAD2/B BRDs to select acetylated lysine among multiple histone post-translational modifications. The ATAD2B BRD can bind acetylated histone ligands that also contain adjacent methylation or phosphorylation marks, while the presence of these modifications significantly weakened the acetyllysine binding activity of the ATAD2 BRD. Our structural studies provide mechanistic insights into how ATAD2/B BRD-binding pocket residues coordinate the acetyllysine group in the context of adjacent post-translational modifications. Furthermore, we investigated how sequence changes in amino acids of the histone ligands impact the recognition of an adjacent acetyllysine residue. Our study highlights how the interplay between multiple combinations of histone modifications influences the reader activity of the ATAD2/B BRDs, resulting in distinct binding modes.

中文翻译：

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组合组蛋白修饰对 ATAD2 和 ATAD2B 溴结构域乙酰赖氨酸识别的影响


ATPase 家族 AAA ⁺ 结构域含有 2 (ATAD2) 蛋白及其旁系同源物 ATAD2B 具有 C 末端溴结构域 (BRD)，可充当组蛋白上乙酰化赖氨酸残基的读取器。使用结构-功能方法，我们研究了 ATAD2/B BRD 在多个组蛋白翻译后修饰中选择乙酰化赖氨酸的能力。 ATAD2B BRD 可以结合也含有相邻甲基化或磷酸化标记的乙酰化组蛋白配体，而这些修饰的存在显着削弱了 ATAD2 BRD 的乙酰赖氨酸结合活性。我们的结构研究为 ATAD2/B BRD 结合口袋残基如何在相邻翻译后修饰的背景下协调乙酰赖氨酸基团提供了机制见解。此外，我们研究了组蛋白配体的氨基酸序列变化如何影响相邻乙酰赖氨酸残基的识别。我们的研究强调了组蛋白修饰的多种组合之间的相互作用如何影响 ATAD2/B BRD 的阅读器活性，从而产生不同的结合模式。