Substrate-Induced Unfolding of Protein Disulfide Isomerase Displaces the Cholera Toxin A1 Subunit from Its Holotoxin
Substrate-Induced Unfolding of Protein Disulfide Isomerase Displaces the Cholera Toxin A1 Subunit from Its Holotoxin
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DOI：
10.1016/j.bpj.2013.11.2668
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发表时间：
2014-01
期刊：
影响因子：
6.7
通讯作者：
M. Taylor;H. Burress;T. Banerjee;Supriyo Ray;David Curtis;S. Tatulian;K. Teter
中科院分区：
文献类型：
--
作者：
M. Taylor;H. Burress;T. Banerjee;Supriyo Ray;David Curtis;S. Tatulian;K. Teter
为了产生细胞病变效应，必须将霍乱毒素(CT)的催化A1亚单位与毒素的其余部分分开。蛋白质二硫键异构酶(PDI)被认为通过作为氧化还原驱动的伴侣，主动打开CTA1亚单位来介导CT的分解。在这里，我们通过同位素编辑的傅里叶变换红外光谱和圆二色谱显示，PDI本身在与CTA1接触时展开。底物诱导的PDI的去折叠为全毒素的解离提供了一种新的分子机制：我们假设展开的PDI的扩展流体动力学半径作为楔子将还原的CTA1从其全毒素中分离出来。PDI的氧化还原酶活性不是CT拆解所必需的，但当PDI被锁定在折叠构象中或当其底物诱导的去折叠因失去伴侣功能而被阻断时，CTA1不发生移位。我们的数据建立了一种新的PDI属性，这是霍乱中毒所必需的，可能与其作为伴侣的功能有关，防止蛋白质聚集。
To generate a cytopathic effect, the catalytic A1 subunit of cholera toxin (CT) must be separated from the rest of the toxin. Protein disulfide isomerase (PDI) is thought to mediate CT disassembly by acting as a redox-driven chaperone that actively unfolds the CTA1 subunit. Here, we show by isotope-edited Fourier transform infrared spectroscopy and circular dichroism that PDI itself unfolds upon contact with CTA1. The substrate-induced unfolding of PDI provides a novel molecular mechanism for holotoxin disassembly: we postulate the expanded hydrodynamic radius of unfolded PDI acts as a wedge to dislodge reduced CTA1 from its holotoxin. The oxidoreductase activity of PDI was not required for CT disassembly, but CTA1 displacement did not occur when PDI was locked in a folded conformation or when its substrate-induced unfolding was blocked due to the loss of chaperone function. Our data establish a new property of PDI that is required for cholera intoxication and may be linked to its function as a chaperone that prevents protein aggregation.