Acetyltransferase p300/CBP associated Factor (PCAF) regulates crosstalk-dependent acetylation of histone H3 by distal site recognition.
Acetyltransferase p300/CBP associated Factor (PCAF) regulates crosstalk-dependent acetylation of histone H3 by distal site recognition.
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DOI：
10.1021/cb5004527
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发表时间：
2015-01-16
影响因子：
4
通讯作者：
Mrksich, Milan
中科院分区：
文献类型：
--
作者：
Kornacki, James R.;Stuparu, Andreea D.;Mrksich, Milan
表观遗传调控部分是由组蛋白翻译后修饰的相关位置决定的，但控制相关修饰的机制尚不完全清楚。相关性由修饰之间的串扰引起，并且通常归因于蛋白质-蛋白质相互作用，该相互作用将酶招募到现有的组蛋白修饰中。在这里，我们报告使用肽阵列来发现乙酰转移酶介导的串扰。我们表明 p300/CBP 相关因子 (PCAF)/GCN5 活性取决于其组蛋白 H3 底物的远端精氨酸残基的存在。 H3 Arg8 的修饰降低了 H3 Lys14 的 PCAF 乙酰化，动力学数据表明精氨酸瓜氨酸化在降低乙酰化方面具有最强的作用。诱变实验表明，PCAF 通过与其催化结构域表面的残基 Tyr640 相互作用来特异性解释 H3 Arg8 修饰，并且这种相互作用通过底物区分来调节 Lys14 乙酰化。 PCAF 可区分修饰肽以及带有 Arg8 修饰的半合成蛋白质和重构核小体。总之，这项工作描述了一种系统地映射串扰的方法，并说明了其在发现和阐明新型 PCAF 串扰中的应用。
Epigenetic regulation is directed, in part, by the correlated placement of histone post-translational modifications, but the mechanisms controlling correlated modifications are incompletely understood. Correlations arise from crosstalk among modifications and are frequently attributed to protein–protein interactions that recruit enzymes to existing histone modifications. Here we report the use of a peptide array to discover acetyltransferase-mediated crosstalks. We show that p300/CBP associated factor (PCAF)/GCN5 activity depends on the presence of a distal arginine residue of its histone H3 substrate. Modifications to H3 Arg8 decrease PCAF acetylation of H3 Lys14, and kinetic data indicate that arginine citrullination has the strongest effect in decreasing acetylation. Mutagenesis experiments demonstrate that PCAF specifically interprets H3 Arg8 modifications through interaction with residue Tyr640 on the surface of its catalytic domain, and this interaction regulates Lys14 acetylation by substrate discrimination. PCAF discriminates modified peptides as well as semisynthetic proteins and reconstituted nucleosomes bearing Arg8 modifications. Together, this work describes a method for systematically mapping crosstalks and illustrates its application to the discovery and elucidation of novel PCAF crosstalks.
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影响因子：
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作者：
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通讯作者：
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