Structural basis for histone and phosphohistone binding by the GCN5 histone acetyltransferase
Structural basis for histone and phosphohistone binding by the GCN5 histone acetyltransferase
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DOI：
10.1016/s1097-2765(03)00288-0
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发表时间：
2003-08-01
期刊：
影响因子：
16
通讯作者：
Marmorstein, R
中科院分区：
文献类型：
--
作者：
Clements, A;Poux, AN;Marmorstein, R
组蛋白上不同的翻译后修饰以特定的模式发生，以介导某些染色体事件。例如，在组蛋白H3上，Ser 10的磷酸化可以增强GCN 5介导的Lys 14乙酰化以促进转录。为了深入了解这种协同作用的机制，我们确定了四膜虫GCN 5（tGCN 5）和辅酶A（CoA）结合未修饰和Ser 10磷酸化的19个残基的组蛋白H3肽（H3 p19和H3 p19 Pi，分别）的结构。tGCN 5/CoA/H3 p19结构揭示了12个氨基酸的核心序列介导与蛋白质的广泛接触，为组蛋白乙酰转移酶的GCN 5/PCAF家族的底物特异性提供了结构基础。与tGCN 5/CoA/H3 p19 Pi结构的比较揭示了磷酸化Ser 10和Thr 11介导显著的组蛋白-蛋白相互作用，并在磷酸化位点的远端使额外的相互作用成核。功能研究表明，组蛋白H3 Thr 11是必要的最佳转录在yGcn 5依赖性启动子需要Ser 10磷酸化。总之，这些研究揭示了一种组蛋白修饰如何调节另一种组蛋白修饰以影响不同的转录信号。
Distinct posttranslational modifications on histones occur in specific patterns to mediate certain chromosomal events. For example, on histone H3, phosphorylation at Ser10 can enhance GCN5-mediated Lys14 acetylation to promote transcription. To gain insight into the mechanism underlying this synergism, we determined the structure of Tetrahymena GCN5 (tGCN5) and coenzyme A (CoA) bound to unmodified and Ser10-phosphorylated 19 residue histone H3 peptides (H3p19 and H3p19Pi, respectively). The tGCN5/CoA/ H3p19 structure reveals that a 12 amino acid core sequence mediates extensive contacts with the protein, providing the structural basis for substrate specificity by the GCN5/PCAF family of histone acetyltransferases. Comparison with the tGCN5/CoA/H3p19Pi structure reveals that phospho-Ser10 and Thr11 mediate significant histone-protein interactions, and nucleate additional interactions distal to the phosphorylation site. Functional studies show that histone H3 Thr11 is necessary for optimal transcription at yGcn5-dependent promoters requiring Ser10 phosphorylation. Together, these studies reveal how one histone modification can modulate another to affect distinct transcriptional signals.