The solution structure of the first PHD finger of autoimmune regulator in complex with non-modified histone H3 tail reveals the antagonistic role of H3R2 methylation
The solution structure of the first PHD finger of autoimmune regulator in complex with non-modified histone H3 tail reveals the antagonistic role of H3R2 methylation
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DOI：
10.1093/nar/gkp166
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发表时间：
2009-05-01
影响因子：
14.9
通讯作者：
Musco, Giovanna
中科院分区：
文献类型：
--
作者：
Chignola, Francesca;Gaetani, Massimiliano;Musco, Giovanna
植物同源结构域（PHD）指常存在于染色质结合蛋白中，并与组蛋白H3 n端尾部结合。自身免疫调节蛋白（AIRE）的突变导致一种罕见的单基因疾病，自身免疫性多内分泌病-念珠菌病-外胚层营养不良（APECED）。AIRE通过其第一个PHD指（AIRE- phd1）直接结合在K4处未甲基化的组蛋白H3尾部（H3K4me0），从而激活组织特异性抗原的表达。在这里，我们展示了AIRE-PHD1与H3K4me0肽复合物的溶液结构，并表明AIRE-PHD1是一个高度特化的非修饰组蛋白H3尾部阅读器，因为组蛋白H3前10个残基的翻译后修饰降低了结合亲和力。特别是，H3R2二甲基化在体外消除AIRE- phd1结合，并降低HEK293细胞中AIRE靶基因的体内活化。观察到的R2甲基化对AIRE-PHD1结合的拮抗作用在H3K4me0组蛋白读取器中是独一无二的，并且代表了非甲基化的H3K4和甲基化的H3R2之间的第一例表观遗传阴性串扰。总的来说，我们的研究结果指出了一个非常特殊的组蛋白代码，负责AIRE-PHD1对非修饰H3尾部的识别，并在原子水平上描述了胸腺抗原表达分子机制的一个关键步骤。
Plant homeodomain (PHD) fingers are often present in chromatin-binding proteins and have been shown to bind histone H3 N-terminal tails. Mutations in the autoimmune regulator (AIRE) protein, which harbours two PHD fingers, cause a rare monogenic disease, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE activates the expression of tissue-specific antigens by directly binding through its first PHD finger (AIRE-PHD1) to histone H3 tails non-methylated at K4 (H3K4me0). Here, we present the solution structure of AIRE-PHD1 in complex with H3K4me0 peptide and show that AIRE-PHD1 is a highly specialized non-modified histone H3 tail reader, as post-translational modifications of the first 10 histone H3 residues reduce binding affinity. In particular, H3R2 dimethylation abrogates AIRE-PHD1 binding in vitro and reduces the in vivo activation of AIRE target genes in HEK293 cells. The observed antagonism by R2 methylation on AIRE-PHD1 binding is unique among the H3K4me0 histone readers and represents the first case of epigenetic negative cross-talk between non-methylated H3K4 and methylated H3R2. Collectively, our results point to a very specific histone code responsible for non-modified H3 tail recognition by AIRE-PHD1 and describe at atomic level one crucial step in the molecular mechanism responsible for antigen expression in the thymus.