Conformational diversity in a yeast prion dictates its seeding specificity
Conformational diversity in a yeast prion dictates its seeding specificity
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DOI：
10.1038/35065632
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发表时间：
2001-03-08
期刊：
影响因子：
64.8
通讯作者：
Weissman, JS
中科院分区：
文献类型：
--
作者：
Chien, P;Weissman, JS
基于朊病毒的遗传的一个令人困惑的特征是，由相同多肽组成的朊病毒可以引起不同的表型（例如脑损伤的分布），即使在遗传上相同的宿主中繁殖也是如此（1-3）。这种菌株多样性的分子基础以及菌株与限制物种间传播的屏障之间的关系仍不清楚。我们已经使用酵母朊病毒现象[PSI+]（4）来研究这些问题，并检查构象差异（1，2，5）在朊病毒菌株中可能具有的作用。我们已经在Sup 35的两个物种（酿酒酵母和白色念珠菌）的朊病毒结构域之间进行了嵌合融合，Sup 35是负责[PSI+]的蛋白质（4，6）。在这里，我们报告说，这种嵌合体形式交替朊病毒株在体内启动时，不同的Sup 35物种的瞬时过表达。类似地，在体外纯化的嵌合体，当接种不同种类的Sup 35纤维，建立和传播不同的淀粉样蛋白构象。这些纤维构象决定了淀粉样蛋白播种的特异性：由S.酿酒酵母纤维有效地催化S. cerevisiae Sup 35，而不是C.白色念珠菌Sup 35，反之亦然。这些和其他考虑（1，2，5，7，8）认为，可遗传的朊病毒株是由朊病毒蛋白本身内的自我繁殖构象差异引起的。此外，这些构象差异似乎与一级结构一致，以确定朊病毒的跨物种屏障传播的倾向。
A perplexing feature of prion-based inheritance is that prions composed of the same polypeptide can evoke different phenotypes (such as distribution of brain lesions), even when propagated in genetically identical hosts(1-3). The molecular basis of this strain diversity and the relationship between strains and barriers limiting transmission between species remain unclear. We have used the yeast prion phenomenon [PSI+](4) to investigate these issues and examine the role that conformational differences(1,2,5) may have in prion strains. We have made a chimaeric fusion between the prion domains of two species (Saccharomyces cerevisae and Candida albicans) of Sup35, the protein responsible for [PSI+](4,6). Here we report that this chimaera forms alternate prion strains in vivo when initiated by transient overexpression of different Sup35 species. Similarly, in vitro the purified chimaera, when seeded with different species of Sup35 fibres, establishes and propagates distinct amyloid conformations. These fibre conformations dictate amyloid seeding specificity: a chimaera seeded by S. cerevisiae fibres efficiently catalyses conversion of S. cerevisiae Sup35 but not of C. albicans Sup35, and vice versa. These and other considerations(1,2,5,7,8) argue that heritable prion strains result from self-propagating conformational differences within the prion protein itself. Moreover, these conformational differences seem to act in concert with the primary structure to determine a prion's propensity for transmission across a species barrier.