Solution structure of the catalytic domain of GCN5 histone acetyltransferase bound to coenzyme A
Solution structure of the catalytic domain of GCN5 histone acetyltransferase bound to coenzyme A
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DOI：
10.1038/21922
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发表时间：
1999-07-01
期刊：
影响因子：
64.8
通讯作者：
Wagner, G
中科院分区：
文献类型：
--
作者：
Lin, YX;Fletcher, CM;Wagner, G
基因转录需要从组蛋白包装中释放出无活性的DNA。在发现第一个转录相关的组蛋白乙酰转移酶四膜虫GCN 5（1）之后，研究表明酵母GCN 5被募集到启动子并引起组蛋白的超乙酰化和靶基因的转录激活（2，3），建立了组蛋白乙酰化和转录激活之间的直接联系。已发现许多其他重要的转录调节因子具有组蛋白乙酰转移酶活性，包括TAFII 230/250、p300/CBP及其相关因子PCAF（4-9）。在这里，我们提出了与辅酶A复合的tGCN 5（残基47-210）的催化结构域的溶液结构。该结构包含两个结构域;氨基末端结构域与其他GCN 5相关N-乙酰基转移酶的结构域相似（10，11），但羧基末端结构域不同。辅酶A结合在两个结构域之间的深疏水口袋中。用组蛋白H3肽滴定后的化学位移变化表明在与辅酶A位点相对的结构域边界处的结合位点。结构数据表明，一个单步乙酰转移反应机制催化的氢键的骨干酰胺基团的亮氨酸126和侧链羧基的一个保守的酸性残基。
Gene transcription requires the release of inactive DNA from its packaging of histone proteins. Following the discovery of the first transcription-associated histone acetyltransferase, tetrahymena GCN5(1), it was shown that yeast GCN5 is recruited to the promoter and causes hyper-acetylation of histones and transcriptional activation of target genes(2,3), establishing a direct connection between histone acetylation and transcriptional activation. Many other important transcription regulators have been found to have histone acetyltransferase activity, including TAFII230/250, p300/CBP and its associated factor PCAF(4-9). Here we present the solution structure of the catalytic domain of tGCN5 (residues 47-210) in complex with coenzyme A. The structure contains two domains; the amino-terminal domain is similar to those of other GCN5-related N-acetyltransferases(10,11) but the carboxy-terminal domain is not. Coenzyme A binds in a deep hydrophobic pocket between the two domains. Chemical shift changes upon titration with histone H3 peptides indicate a binding site at the domain boundary opposite to the coenzyme A site. The structural data indicate a single-step acetyl-transfer reaction mechanism catalysed by a hydrogen bond to the backbone amide group of leucine 126 and the side-chain carboxyl group of a conserved acidic residue.