Crystal structure and mechanism of histone acetylation of the yeast GCN5 transcriptional coactivator
Crystal structure and mechanism of histone acetylation of the yeast GCN5 transcriptional coactivator
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DOI：
10.1073/pnas.96.16.8931
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发表时间：
1999-08-03
影响因子：
11.1
通讯作者：
Marmorstein, R
中科院分区：
文献类型：
--
作者：
Trievel, RC;Rojas, JR;Marmorstein, R
酵母GCN 5（yGCN 5）转录辅激活因子的功能是作为组蛋白乙酰转移酶（HAT）来促进转录激活。在这里，我们提出了高分辨率的yGCN 5的HAT结构域的晶体结构，并探测保守的谷氨酸残基的功能的重要性。该结构揭示了与AcCoA相关的中心蛋白质核心。结合，似乎在N-乙酰转移酶的超家族中结构保守，包括酵母组蛋白乙酰转移酶1和粘质沙雷氏菌氨基糖苷3-N-乙酰转移酶。一个明显的裂缝躺在这个核心之上，两侧的N-和C-末端区域，没有显示N-乙酰转移酶内的序列保守性，被牵连的跨物种保护和诱变研究是一个网站组蛋白底物结合和催化。位于这个裂缝的底部是一个保守的谷氨酸残基（E173），它在组蛋白乙酰化中起着重要的催化作用。E173 Q突变体yGCN 5蛋白的功能分析暗示谷氨酸173作为催化的一般基础发挥作用。总之，yGCN 5结构与功能性削弱yGCN 5突变的相关性提供了一个范例，用于理解越来越多的转录调节因子的结构/功能关系，这些转录调节因子起组蛋白乙酰转移酶的作用。
The yeast GCN5 (yGCN5) transcriptional coactivator functions as a histone acetyltransferase (HAT) to promote transcriptional activation. Here, we present the high resolution crystal structure of the HAT domain of yGCN5 and probe the functional importance of a conserved glutamate residue. The structure reveals a central protein core associated with AcCoA. binding that appears to be structurally conserved among a superfamily of N-acetyltransferases, including yeast histone acetyltransferase 1 and Serratia marcescens aminoglycoside 3-N-acetyltransferase. A pronounced cleft lying above this core, and flanked by N- and C-terminal regions that show no sequence conservation within N-acetyltransferase enzymes, is implicated by cross-species conservation and mutagenesis studies to be a site for histone substrate binding and catalysis. Located at the bottom of this cleft is a conserved glutamate residue (E173) that is in position to play an important catalytic role in histone acetylation. Functional analysis of an E173Q mutant yGCN5 protein implicates glutamate 173 to function as a general base for catalysis. Together, a correlation of the yGCN5 structure with functionally debilitating yGCN5 mutations provides a paradigm for understanding the structure/function relationships of the growing number of transcriptional regulators that function as histone acetyltransferase enzymes.