1] European Molecular Biology Laboratory, Grenoble, France. [2] Unit for Virus Host-Cell Interactions, University of Grenoble Alpes, European Molecular Biology Laboratory-Centre National de la Recherche Scientifique, Grenoble, France. [3].
Nat Struct Mol Biol. 2013 Sep;20(9):1040-6. doi: 10.1038/nsmb.2642. Epub 2013 Aug 11.
CBP and p300 are histone acetyltransferases (HATs) that associate with and acetylate transcriptional regulators and chromatin. Mutations in their catalytic 'cores' are linked to genetic disorders, including cancer. Here we present the 2.8-Å crystal structure of the catalytic core of human p300 containing its bromodomain, CH2 region and HAT domain. The structure reveals that the CH2 region contains a discontinuous PHD domain interrupted by a RING domain. The bromodomain, PHD, RING and HAT domains adopt an assembled configuration with the RING domain positioned over the HAT substrate-binding pocket. Disease mutations that disrupt RING attachment led to upregulation of HAT activity, thus revealing an inhibitory role for this domain. The structure provides a starting point for understanding how chromatin-substrate targeting and HAT regulation are coupled and why mutations in the p300 core lead to dysregulation.
CBP 和 p300 是组蛋白乙酰转移酶 (HATs)，它们与转录调节剂和染色质结合并乙酰化它们。其催化“核心”的突变与包括癌症在内的遗传疾病有关。在这里，我们呈现了包含其溴结构域、CH2 区域和 HAT 结构域的人 p300 催化核心的 2.8Å 晶体结构。该结构表明，CH2 区域包含一个不连续的 PHD 结构域，被一个 RING 结构域打断。溴结构域、PHD、RING 和 HAT 结构域采用组装配置，RING 结构域位于 HAT 底物结合口袋上方。破坏 RING 附着的疾病突变导致 HAT 活性上调，从而揭示了该结构域的抑制作用。该结构为理解染色质-底物靶向和 HAT 调节如何偶联以及为什么 p300 核心的突变导致失调提供了一个起点。
