Structural basis of molecular recognition of helical histone H3 tail by PHD finger domains.
Structural basis of molecular recognition of helical histone H3 tail by PHD finger domains.
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DOI：
10.1042/bcj20161053
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发表时间：
2017-05-04
期刊：
影响因子：
--
通讯作者：
Ciulli A
中科院分区：
文献类型：
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作者：
Bortoluzzi A;Amato A;Lucas X;Blank M;Ciulli A
植物同源域(PHD)指是最大的表观遗传域家族之一，最初被描述为甲基化H3K4的阅读器。PHD读出的组蛋白翻译后修饰一直是密集研究的主题；然而，对组蛋白尾巴本身二级结构特征的识别知之甚少。我们解决了与锌指2A相邻的溴结构域的PHD指的晶体结构[BAZ2A，也称为TIP5(TTF-I/相互作用蛋白5)]与未修饰的N端组蛋白H3尾巴形成的络合物。在K4之后，多肽以螺旋折回构象结合，这是由蛋白质表面的酸性斑块诱导的，酸性斑块阻止了延伸构象中的多肽结合。结构生物信息学分析发现，一个保守的天冬氨酸/谷氨酸残基，我们称之为‘酸性墙’，发现与保守的Trp相互排斥的K4Me识别。BAZ2A和同源BAZ2B酸性壁片上电荷的中和或反转削弱了H3结合。我们确定了H3上的简单突变，这些突变显著地增强或减少了结合，这是它们稳定或不稳定H3螺旋性的结果。我们的工作揭示了PHD手指结合螺旋H3尾巴的结构基础，并表明组蛋白尾巴中二级结构基序的分子识别可能代表着表观遗传过程中的额外一层调控。
The plant homeodomain (PHD) fingers are among the largest family of epigenetic domains, first characterized as readers of methylated H3K4. Readout of histone post-translational modifications by PHDs has been the subject of intense investigation; however, less is known about the recognition of secondary structure features within the histone tail itself. We solved the crystal structure of the PHD finger of the bromodomain adjacent to zinc finger 2A [BAZ2A, also known as TIP5 (TTF-I/interacting protein 5)] in complex with unmodified N-terminal histone H3 tail. The peptide is bound in a helical folded-back conformation after K4, induced by an acidic patch on the protein surface that prevents peptide binding in an extended conformation. Structural bioinformatics analyses identify a conserved Asp/Glu residue that we name ‘acidic wall’, found to be mutually exclusive with the conserved Trp for K4Me recognition. Neutralization or inversion of the charges at the acidic wall patch in BAZ2A, and homologous BAZ2B, weakened H3 binding. We identify simple mutations on H3 that strikingly enhance or reduce binding, as a result of their stabilization or destabilization of H3 helicity. Our work unravels the structural basis for binding of the helical H3 tail by PHD fingers and suggests that molecular recognition of secondary structure motifs within histone tails could represent an additional layer of regulation in epigenetic processes.