Structure and function of the histone chaperone CIA/ASF1 complexed with histones H3 and H4
Structure and function of the histone chaperone CIA/ASF1 complexed with histones H3 and H4
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DOI：
10.1038/nature05613
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发表时间：
2007-03-15
期刊：
影响因子：
64.8
通讯作者：
Senda, Toshiya
中科院分区：
文献类型：
--
作者：
Natsume, Ryo;Eitoku, Masamitsu;Senda, Toshiya
CIA（CCG 1-interacting factor A）/ASF 1是真核生物中最保守的组蛋白伴侣，通过酵母遗传筛选被遗传鉴定为抗沉默功能的因子（Asf 1）（1）。此后不久，CIA-组蛋白-H3-H4复合物作为组蛋白伴侣CAF-1刺激剂从果蝇中分离出来（2）。人CIA-I/II（ASF 1a/B）被鉴定为与通用转录起始因子TFIID 3 -5中CCG 1的溴结构域（乙酰化组蛋白识别结构域）相互作用的组蛋白伴侣。深入的研究表明，CIA/ASF 1通过与人类细胞6和酵母7中的另一组蛋白伴侣形成复合物来介导核小体组装，并参与酵母中的DNA复制1，2，转录4，8 - 10，DNA修复1，2，11，1,2和沉默/反沉默（1，2，8，13 -15）。CIA/ASF 1被证明是增殖人类细胞中可溶性组蛋白的主要储存伴侣（6，16）。尽管所有这些生物化学和生物学功能分析，CIA/ASF 1的核小体组装/拆卸活性的结构-功能关系仍然难以捉摸。在这里，我们报告的晶体结构，在2.7埃的分辨率，CIA-I与组蛋白H3和H4的复合物。该结构显示了组蛋白H3 - H4二聚体与另一组蛋白H3 - H4二聚体和CIA-I的互斥相互作用。组蛋白H4的羧基端β链通过大的构象变化将其配偶体从组蛋白H2 A的β链变为CIA-I的β链。体外功能分析表明，CIA-I具有破坏组蛋白H3 - H4四聚体的活性。具有弱组蛋白H3-H4二聚体结合活性的突变体对与转录相关的细胞过程显示出关键的功能效应。CIA/ASF 1的组蛋白H3-H4四聚体破坏活性和CIA/ASF 1-组蛋白-H3-H4二聚体复合物的晶体结构应提供对核小体组装/拆卸和核小体半保守复制机制的见解。
CIA(CCG1-interacting factor A)/ASF1, which is the most conserved histone chaperone among the eukaryotes, was genetically identified as a factor for an anti-silencing function (Asf1)(1) by yeast genetic screening. Shortly after that, the CIA-histone-H3-H4 complex was isolated from Drosophila as a histone chaperone CAF-1 stimulator(2). Human CIA-I/II (ASF1a/b) was identified as a histone chaperone that interacts with the bromodomain - an acetylated-histone-recognizing domain - of CCG1, in the general transcription initiation factor TFIID3-5. Intensive studies have revealed that CIA/ASF1 mediates nucleosome assembly by forming a complex with another histone chaperone in human cells 6 and yeast 7, and is involved in DNA replication 1,2, transcription 4,8 - 10, DNA repair 1,2,11,12 and silencing/ anti-silencing(1,2,8,13-15) in yeast. CIA/ASF1 was shown as a major storage chaperone for soluble histones in proliferating human cells(6,16). Despite all these biochemical and biological functional analyses, the structure - function relationship of the nucleosome assembly/disassembly activity of CIA/ASF1 has remained elusive. Here we report the crystal structure, at 2.7 angstrom resolution, of CIA-I in complex with histones H3 and H4. The structure shows the histone H3 - H4 dimer's mutually exclusive interactions with another histone H3 - H4 dimer and CIA-I. The carboxy-terminal beta-strand of histone H4 changes its partner from the beta-strand in histone H2A to that of CIA-I through large conformational change. In vitro functional analysis demonstrated that CIA-I has a histone H3 - H4 tetramer-disrupting activity. Mutants with weak histone H3-H4 dimer binding activity showed critical functional effects on cellular processes related to transcription. The histone H3-H4 tetramer-disrupting activity of CIA/ASF1 and the crystal structure of the CIA/ASF1-histone-H3-H4 dimer complex should give insights into mechanisms of both nucleosome assembly/disassembly and nucleosome semi-conservative replication.