Molecular basis for Gcn5/PCAF histone acetyltransferase selectivity for histone and nonhistone substrates
Molecular basis for Gcn5/PCAF histone acetyltransferase selectivity for histone and nonhistone substrates
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DOI：
10.1021/bi035632n
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发表时间：
2003-12-16
期刊：
影响因子：
2.9
通讯作者：
Marmorstein, R
中科院分区：
文献类型：
--
作者：
Poux, AN;Marmorstein, R
组蛋白乙酰转移酶 (HAT) 蛋白通常对带有赖氨酸的蛋白底物表现出高度的特异性。我们之前报道了四膜虫 Gcn5 HAT 蛋白 (tGcn5) 与其首选组蛋白 H3 底物结合的结构，揭示了 HAT 蛋白 Gcn5/PCAF 家族的底物结合模式。有趣的是，Gcn5/PCAF HAT 家族具有乙酰化不同同源位点内赖氨酸残基的显着能力，例如分别在组蛋白 H3、H4 和 p53 的赖氨酸 14、8 和 320 周围发现的赖氨酸残基。为了研究其分子基础，我们现在报告了与 19 残基组蛋白 H4 和 p53 肽结合的 tGcn5 的晶体结构。将这些结构与与组蛋白 H3 结合的 tGcn5 进行比较表明，Gcn5/PCAF HAT 可以通过利用与赖氨酸靶标和具有相关化学性质的两个 C 端残基的类似相互作用来适应不同的底物，表明这些相互作用在 Gcn5/PCAF 底物结合选择性中发挥一般作用。相反，虽然组蛋白 H3 复合物显示出与 tGcn5 和目标赖氨酸 N 端肽残基的广泛相互作用，但组蛋白 H4 和 p53 中的相应残基是无序的，这表明 N 端底物区域在 Gcn5/PCAF HAT 蛋白对组蛋白 H3 的亲和力增强中发挥着重要作用。总之，这些研究为理解 HAT 蛋白的底物选择性提供了一个框架。
Histone acetyltransferase (HAT) proteins often exhibit a high degree of specificity for lysine-bearing protein substrates. We have previously reported on the structure of the Tetrahymena Gcn5 HAT protein (tGcn5) bound to its preferred histone H3 substrate, revealing the mode of substrate binding by the Gcn5/PCAF family of HAT proteins. Interestingly, the Gcn5/PCAF HAT family has a remarkable ability to acetylate lysine residues within diverse cognate sites such as those found around lysines 14, 8, and 320 of histones H3, H4, and p53, respectively. To investigate the molecular basis for this, we now report on the crystal structures of tGcn5 bound to 19-residue histone H4 and p53 peptides. A comparison of these structures with tGcn5 bound to histone H3 reveals that the Gcn5/PCAF HATs can accommodate divergent substrates by utilizing analogous interactions with the lysine target and two C-terminal residues with a related chemical nature, suggesting that these interactions play a general role in Gcn5/PCAF substrate binding selectivity. In contrast, while the histone H3 complex shows extensive interactions with tGcn5 and peptide residues N-terminal to the target lysine, the corresponding residues in histone H4 and p53 are disordered, suggesting that the N-terminal substrate region plays an important role in the enhanced affinity of the Gcn5/PCAF HAT proteins for histone H3. Together, these studies provide a framework for understanding the substrate selectivity of HAT proteins.