Assembly and function of a bacterial genotoxin
Assembly and function of a bacterial genotoxin
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DOI：
10.1038/nature02532
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发表时间：
2004-05-27
期刊：
影响因子：
64.8
通讯作者：
Stebbins, CE
中科院分区：
文献类型：
--
作者：
Nesic, D;Hsu, Y;Stebbins, CE
三方细胞致死性膨胀毒素(CDT)诱导真核细胞周期停滞和细胞凋亡(1，2)。亚基cdtA和cdtC与核酸酶cdtB结合形成全毒素，将cdtB转位到宿主细胞中，在宿主细胞中，它通过产生DNA损伤而起到遗传毒素的作用(3-7)。我们发现杜氏嗜血杆菌全毒素的晶体结构表明，CDT由DNase-I家族的一个酶组成，结合在两个类似蓖麻毒素的凝集素结构域上。CdtA、CdtB和CdtC形成具有三个相互依赖的分子界面的三元络合物，其特征是球状和广泛的非球状相互作用。凝集素亚基形成一个深深的凹槽，高度芳香的表面，我们证明这是毒性的关键。全息毒素通过CDtC亚基的非球状延伸而拥有CDtB活性部位的空间区块，我们鉴定了CDtB中可能的DNA结合残基是毒素活性所必需的。
The tripartite cytolethal distending toxin (CDT) induces cell cycle arrest and apoptosis in eukaryotic cells(1,2). The subunits CdtA and CdtC associate with the nuclease CdtB to form a holotoxin that translocates CdtB into the host cell, where it acts as a genotoxin by creating DNA lesions(3-7). Here we show that the crystal structure of the holotoxin from Haemophilus ducreyi reveals that CDT consists of an enzyme of the DNase-I family, bound to two ricin-like lectin domains. CdtA, CdtB and CdtC form a ternary complex with three interdependent molecular interfaces, characterized by globular, as well as extensive non-globular, interactions. The lectin subunits form a deeply grooved, highly aromatic surface that we show to be critical for toxicity. The holotoxin possesses a steric block of the CdtB active site by means of a non-globular extension of the CdtC subunit, and we identify putative DNA binding residues in CdtB that are essential for toxin activity.