Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université Bordeaux 2 «Victor Segalen», 1 rue Camille Saint Saëns, 33077 Bordeaux, France.
J Mol Biol. 2011 Sep 9;412(1):137-52. doi: 10.1016/j.jmb.2011.07.009. Epub 2011 Jul 18.
The folding and interactions of amyloid proteins are at the heart of the debate as to how these proteins may or may not become toxic to their host. Although little is known about this issue, the structure seems to be clearly involved with effects on molecular events. To understand how an amyloid may be toxic, we previously generated a yeast toxic amyloid (mutant 8) from the nontoxic HET-s((218-289)) prion domain of Podospora anserina. Here, we performed a comprehensive structure-toxicity study by mutating individually each of the 10 mutations found in mutant 8. The study of the library of new mutants generated allowed us to establish a clear link between Fourier transform infrared antiparallel signature and amyloid toxicity. All of the mutants that form parallel β-sheets are not toxic. Double mutations may be sufficient to shift a parallel structure to antiparallel amyloids, which are toxic to yeast. Our findings also suggest that the toxicity of antiparallel structured mutants may be linked to interaction with membranes.
淀粉样蛋白的折叠和相互作用是争论的核心，即这些蛋白质如何可能对宿主有毒，也可能没有毒性。尽管对此知之甚少，但结构似乎显然与分子事件的影响有关。为了了解淀粉样蛋白如何具有毒性，我们之前从 Podospora anserina 的无毒 HET-s((218-289)) 朊病毒结构域中生成了一种酵母毒性淀粉样蛋白（突变体 8）。在这里，我们通过单独突变突变体 8 中发现的 10 个突变中的每一个，进行了全面的结构-毒性研究。对生成的新突变体文库的研究使我们能够在傅里叶变换红外反平行特征与淀粉样蛋白毒性之间建立明确的联系。所有形成平行 β-折叠的突变体都没有毒性。双突变可能足以将平行结构转变为具有毒性的反平行淀粉样蛋白。我们的研究结果还表明，反平行结构突变体的毒性可能与与膜的相互作用有关。
