Hefei National Laboratory for Physical Science at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China.
National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China.
FEBS J. 2017 Oct;284(20):3422-3436. doi: 10.1111/febs.14198. Epub 2017 Sep 12.
The acetylation of lysine 56 of histone H3 (H3K56ac) enhances the binding affinity of histone chaperones to H3-H4 dimers. CREB-binding protein (CBP) possesses a bromodomain that recognizes H3K56 acetylation. CBP also possesses a histone acetyltransferase (HAT) domain, which has been shown to promote H3K56 acetylation of free histones to facilitate delivery of replication-dependent chaperones to acetylated histones for chromatin assembly. However, the mechanism by which the CBP bromodomain recognizes H3K56ac and the context in which such recognition occurs remain elusive. Here, we solved the crystal structure of the CBP bromodomain in complex with an H3K56ac peptide. Our data demonstrate that the CBP bromodomain recognizes H3K56ac with high affinity. Structural and affinity analyses reveal that the CBP bromodomain prefers an aromatic residue at the -2 position and an arginine at the -4 position from the acetyl-lysine, and that the CBP bromodomain selectively recognizes an extended conformation of the H3 αN helix that contains H3K56ac. We also demonstrate that the CBP bromodomain binds to H3K56ac in a recombinant H3-H4 dimer but not in a mono-nucleosome. Our results suggest that the CBP bromodomain selectively recognizes an extended conformation of the K56-acetylated H3 α region within an H3-H4 dimer, which is expected to facilitate the HAT activity of CBP for subsequent H3K56 acetylation of free histones.
Coordinates of the CBP bromodomain in complex with H3K56ac as described in this article have been deposited in the PDB with accession number 5GH9.
组蛋白 H3 赖氨酸 56 的乙酰化（H3K56ac）增强了组蛋白伴侣与 H3-H4 二聚体的结合亲和力。CREB 结合蛋白（CBP）具有一个溴结构域，可识别 H3K56 乙酰化。CBP 还具有一个组蛋白乙酰转移酶（HAT）结构域，该结构域已被证明可促进游离组蛋白的 H3K56 乙酰化，以促进复制依赖性伴侣蛋白向乙酰化组蛋白的传递，用于染色质组装。然而，CBP 溴结构域识别 H3K56ac 的机制以及这种识别发生的背景仍然难以捉摸。在这里，我们解决了 CBP 溴结构域与 H3K56ac 肽复合物的晶体结构。我们的数据表明，CBP 溴结构域以高亲和力识别 H3K56ac。结构和亲和力分析表明，CBP 溴结构域更喜欢在乙酰赖氨酸的-2 位和-4 位上带有芳香族残基，并且 CBP 溴结构域选择性地识别包含 H3K56ac 的 H3 αN 螺旋的扩展构象。我们还证明，CBP 溴结构域在重组 H3-H4 二聚体中但不在单核小体中结合 H3K56ac。我们的结果表明，CBP 溴结构域选择性地识别 H3-H4 二聚体中 K56-乙酰化 H3 α 区域的扩展构象，这有望促进 CBP 的 HAT 活性，以随后对游离组蛋白进行 H3K56 乙酰化。
本文中描述的 CBP 溴结构域与 H3K56ac 复合物的坐标已被存入 PDB，登录号为 5GH9。
