Spontaneous variants of the [RNQ+] prion in yeast demonstrate the extensive conformational diversity possible with prion proteins.
Spontaneous variants of the [RNQ+] prion in yeast demonstrate the extensive conformational diversity possible with prion proteins.
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DOI：
10.1371/journal.pone.0079582
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
True HL
中科院分区：
文献类型：
--
作者：
Huang VJ;Stein KC;True HL
朊病毒株（或变体）是由单一多肽序列产生的结构上不同的淀粉样蛋白构象。在哺乳动物朊病毒疾病中，朊病毒株的存在已得到充分证明。在许多情况下，朊病毒株表现为疾病进展和病理学的变化，并且在某些情况下，这些朊病毒株还显示出不同的生化特性。然而，朊病毒繁殖的基础和淀粉样蛋白的构象可能性的程度仍然在很大程度上不确定。酵母中的朊病毒蛋白也能够维持多种自繁殖结构，这为朊病毒生物学提供了许多见解。在这里，我们探讨了巨大的结构多样性的酵母朊病毒[RNQ+]在酿酒酵母。我们在体内筛选[RNQ+]的形成，使我们能够计算自发形成的速率为~2.96x10-6，并成功分离出几种不同的[RNQ+]变体。通过一套全面的生化和生物学分析，我们表明这些朊病毒变体确实是新的。没有任何一种特性或一组特性，包括聚集体的稳定性和大小，足以解释朊病毒变异体的物理基础和范围及其产生的细胞表型。此外，我们分离的所有[RNQ+]变体都能够促进酵母朊病毒[PSI+]的从头形成，这是翻译终止的表观遗传决定因素。这支持了[RNQ+]在调节[PSI+]的形成中作为功能性淀粉样蛋白以在酵母群体内产生表型多样性并促进适应的假设。总的来说，这项工作显示了广泛的可用淀粉样蛋白构象，从而扩大了研究相互作用，以调节不同的聚集体结构的传播的复杂因素的基础。
Prion strains (or variants) are structurally distinct amyloid conformations arising from a single polypeptide sequence. The existence of prion strains has been well documented in mammalian prion diseases. In many cases, prion strains manifest as variation in disease progression and pathology, and in some cases, these prion strains also show distinct biochemical properties. Yet, the underlying basis of prion propagation and the extent of conformational possibilities available to amyloidogenic proteins remain largely undefined. Prion proteins in yeast that are also capable of maintaining multiple self-propagating structures have provided much insight into prion biology. Here, we explore the vast structural diversity of the yeast prion [RNQ+] in Saccharomyces cerevisiae. We screened for the formation of [RNQ+] in vivo, allowing us to calculate the rate of spontaneous formation as ~2.96x10-6, and successfully isolate several different [RNQ+] variants. Through a comprehensive set of biochemical and biological analyses, we show that these prion variants are indeed novel. No individual property or set of properties, including aggregate stability and size, was sufficient to explain the physical basis and range of prion variants and their resulting cellular phenotypes. Furthermore, all of the [RNQ+] variants that we isolated were able to facilitate the de novo formation of the yeast prion [PSI+], an epigenetic determinant of translation termination. This supports the hypothesis that [RNQ+] acts as a functional amyloid in regulating the formation of [PSI+] to produce phenotypic diversity within a yeast population and promote adaptation. Collectively, this work shows the broad spectrum of available amyloid conformations, and thereby expands the foundation for studying the complex factors that interact to regulate the propagation of distinct aggregate structures.
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