Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, Vermont 05405, United States.
Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, Vermont 05446, United States.
J Med Chem. 2024 May 23;67(10):8186-8200. doi: 10.1021/acs.jmedchem.4c00210. Epub 2024 May 11.
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.
ATP 酶家族 AAA 结构域包含蛋白 2（ATAD2）及其同源蛋白 ATAD2B 具有 C 端溴结构域（BRD），可作为组蛋白上乙酰化赖氨酸残基的阅读器。本研究采用结构功能方法，研究了 ATAD2/B BRD 在多种组蛋白翻译后修饰中选择乙酰化赖氨酸的能力。ATAD2B BRD 可结合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著削弱了 ATAD2 BRD 对乙酰赖氨酸的结合活性。本研究的结构研究提供了关于 ATAD2/B BRD 结合口袋残基如何在相邻翻译后修饰背景下协调乙酰赖氨酸基团的机制见解。此外，我们还研究了组蛋白配体中氨基酸序列变化如何影响相邻乙酰赖氨酸残基的识别。本研究强调了多种组蛋白修饰组合之间的相互作用如何影响 ATAD2/B BRD 的读取器活性，从而导致不同的结合模式。
