Molecular basis of histone H3K4me3 recognition by ING4
Molecular basis of histone H3K4me3 recognition by ING4
复制标题
DOI：
10.1074/jbc.m710020200
复制
发表时间：
2008-06-06
影响因子：
4.8
通讯作者：
Blanco, Francisco J.
中科院分区：
文献类型：
--
作者：
Palacios, Alicia;Munoz, Ines G.;Blanco, Francisco J.
生长抑制剂（ING）家族肿瘤抑制因子由5个参与染色质重塑的同源蛋白组成。它们构成不同乙酰化和去乙酰化复合物的一部分，并被认为通过它们保守的植物同源结构域（PHD）识别H3K4me3（组蛋白3尾部三甲基化的K4），将它们引导到染色质的特定区域。我们已经确定了ING4-PHD与H3K4me3结合的晶体结构，揭示了一个通过多次相互作用稳定的紧密配合物。核磁共振表明，参与肽结合的PHD区域的骨干迁移率降低，并且结合亲和力取决于组蛋白尾部长度。热力学分析表明，有利于甲基化赖氨酸的区分是熵驱动的，与已经描述的色域相反。ING4与ING2识别H3K4me3的分子基础不同，这与它们对甲基化组蛋白尾部的不同亲和力是一致的。这些差异表明这两个ING家族成员在转录调控中具有不同的作用，因为它们在染色质上募集的复合物具有拮抗作用。我们的研究结果说明了PHD手指作为组蛋白编码阅读器的多功能性。
The inhibitors of growth (ING) family of tumor suppressors consists of five homologous proteins involved in chromatin remodeling. They form part of different acetylation and deacetylation complexes and are thought to direct them to specific regions of the chromatin, through the recognition of H3K4me3 (trimethylated K4 in the histone 3 tail) by their conserved plant homeodomain (PHD). We have determined the crystal structure of ING4-PHD bound to H3K4me3, which reveals a tight complex stabilized by numerous interactions. NMR shows that there is a reduction in the backbone mobility on the regions of the PHD that participate in the peptide binding, and binding affinities differ depending on histone tail lengths Thermodynamic analysis reveals that the discrimination in favor of methylated lysine is entropydriven, contrary to what has been described for chromodomains. The molecular basis of H3K4me3 recognition by ING4 differs from that of ING2, which is consistent with their different affinities for methylated histone tails. These differences suggest a distinct role in transcriptional regulation for these two ING family members because of the antagonistic effect of the complexes that they recruit onto chromatin. Our results illustrate the versatility of PHD fingers as readers of the histone code.