Cooperative binding of two acetylation marks on a histone tail by a single bromodomain
Cooperative binding of two acetylation marks on a histone tail by a single bromodomain
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DOI：
10.1038/nature08397
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发表时间：
2009-10-01
期刊：
影响因子：
64.8
通讯作者：
Petosa, Carlo
中科院分区：
文献类型：
--
作者：
Moriniere, Jeanne;Rousseaux, Sophie;Petosa, Carlo
在许多与染色质相关的过程中，关键的一步是通过效应模块识别组蛋白翻译后修饰，例如皇家(1，2)家族的溴结构域和染色质样结构域。虽然效应器介导的单一翻译后修饰的识别是很好的特征(3)，但细胞如何实现带有多个修饰的组蛋白的组合读出却知之甚少。一种机制涉及由链接的效应器模块(4)进行的多价结合。例如，人TATA结合蛋白相关因子-1(TAF1)的串联溴结构域与双乙酰化组蛋白H4尾部结合得比与单乙酰化组蛋白H4尾部结合得更好，这种协同效应归因于每个溴结构域与一个乙酰赖氨酸标记结合(5)。在这里，我们报告了一种不同的组合读出小鼠TAF1同源物BRDT的机制，BRDT是BET蛋白家族中睾丸特异的成员(6)。BRDT与高乙酰化组蛋白H4相关7)，并与精子发生过程中组蛋白超乙酰化后显著的染色质重塑有关，精子发生阶段是减数分裂后的生殖细胞成熟为完全分化的精子(7-10)。值得注意的是，我们发现BRDT的单个溴结构域(BD1)负责选择性识别带有两个或更多乙酰化标记的组蛋白H4尾部。BD1与双乙酰化H4尾巴结合的晶体结构表明，两个乙酰赖氨酸残基如何与一个结合口袋相互作用。基于结构的突变降低了BD1对双乙酰化尾巴的选择性，在体内破坏了BRDT与乙酰化染色质的结合。结构分析表明，其他与染色质相关的蛋白可能具有类似的配体识别模式，包括酵母Bdf1、人TAF1和人CBP/p300(分别也称为CREBBP和EP300)。我们的发现描述了一种新的组合读出组蛋白修饰的机制，其中一个效应器模块与组蛋白尾部的两个标记作为复合结合表位。
A key step in many chromatin-related processes is the recognition of histone post-translational modifications by effector modules such as bromodomains and chromo-like domains of the Royal family(1,2). Whereas effector-mediated recognition of single post-translational modifications is well characterized(3), how the cell achieves combinatorial readout of histones bearing multiple modifications is poorly understood. One mechanism involves multivalent binding by linked effector modules(4). For example, the tandem bromodomains of human TATA-binding protein-associated factor-1 (TAF1) bind better to a diacetylated histone H4 tail than to monoacetylated tails, a cooperative effect attributed to each bromodomain engaging one acetyl-lysine mark(5). Here we report a distinct mechanism of combinatorial readout for the mouse TAF1 homologue Brdt, a testis-specific member of the BET protein family(6). Brdt associates with hyperacetylated histone H4 (ref. 7) and is implicated in the marked chromatin remodelling that follows histone hyperacetylation during spermiogenesis, the stage of spermatogenesis in which post-meiotic germ cells mature into fully differentiated sperm(7-10). Notably, we find that a single bromodomain (BD1) of Brdt is responsible for selectively recognizing histone H4 tails bearing two or more acetylation marks. The crystal structure of BD1 bound to a diacetylated H4 tail shows how two acetyl-lysine residues cooperate to interact with one binding pocket. Structure-based mutagenesis that reduces the selectivity of BD1 towards diacetylated tails destabilizes the association of Brdt with acetylated chromatin in vivo. Structural analysis suggests that other chromatin-associated proteins may be capable of a similar mode of ligand recognition, including yeast Bdf1, human TAF1 and human CBP/p300 (also known as CREBBP and EP300, respectively). Our findings describe a new mechanism for the combinatorial readout of histone modifications in which a single effector module engages two marks on a histone tail as a composite binding epitope.