Extensive diversity of prion strains is defined by differential chaperone interactions and distinct amyloidogenic regions.
Extensive diversity of prion strains is defined by differential chaperone interactions and distinct amyloidogenic regions.
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DOI：
10.1371/journal.pgen.1004337
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发表时间：
2014-05
期刊：
影响因子：
4.5
通讯作者：
True HL
中科院分区：
文献类型：
--
作者：
Stein KC;True HL
与各种无关疾病相关的淀粉样蛋白通常能够形成几种不同的自我模板构象。在普恩病毒疾病中，这些不同的结构被称为普恩病毒株(或变种)，使疾病的病理和传播发生了巨大的变化。聚集体的稳定性已被发现是不同病毒株不同病理后果的关键决定因素。然而，在很大程度上还不清楚哪些其他因素可能会解释聚集倾向蛋白的广泛表型差异。在这里，我们研究了一组[RNQ+]蛋白的酵母蛋白变体，它们诱导另一种称为[PSI+]的酵母蛋白形成的能力不同。值得注意的是，我们发现[RNQ+]变体需要Rnq1蛋白的不同、不连续的区域来进行Pron繁殖和[PSI+]诱导。这包括Rnq1正则的普利子形成结构域之外的区域。值得注意的是，这种差异并没有导致聚集体稳定性的变化。我们的分析还显示，这些[RNQ+]变体与伴侣Sis1相互作用的能力存在显著差异。因此，我们的工作表明，不同淀粉样变性区域的不同影响以及与宿主辅助因子的相互作用是不同聚集体结构的表型后果的关键决定因素。这有助于揭示复杂的相互依赖的因素，这些因素影响特定的淀粉样蛋白结构如何决定疾病的病理和进展。蛋白质构象紊乱，包括许多神经退行性疾病，当蛋白质错误折叠并经历构象变化形成自模板聚集体时，称为淀粉样蛋白。有趣的是，在这些疾病中错误折叠的蛋白质往往会形成各种各样不同的聚集体结构。在普恩病毒病中，这些不同的淀粉样蛋白构象称为普恩病毒株。Pron菌株的不同构象负责调节疾病的进展、病理和传播。以前对酵母蛋白的研究已经为不同的蛋白构象如何引起这种表型变异提供了巨大的洞察力。在这里，我们使用了一组[RNQ+]Prion变体来展示在不同聚集结构的传播中涉及的复杂的相互作用网络。我们发现，Rnq1的几个不同的不相邻区域，甚至在Prion形成区域之外，对[RNQ+]Prion的不同变体的传播做出了不同的贡献。此外，我们的数据支持[RNQ+]变体与分子伴侣Sis1存在差异相互作用的假设。这些数据强烈表明，不同聚集体构象的不同表型表现取决于一组独特的初级结构元素和与宿主辅因子的不同相互作用。
Amyloidogenic proteins associated with a variety of unrelated diseases are typically capable of forming several distinct self-templating conformers. In prion diseases, these different structures, called prion strains (or variants), confer dramatic variation in disease pathology and transmission. Aggregate stability has been found to be a key determinant of the diverse pathological consequences of different prion strains. Yet, it remains largely unclear what other factors might account for the widespread phenotypic variation seen with aggregation-prone proteins. Here, we examined a set of yeast prion variants of the [RNQ+] prion that differ in their ability to induce the formation of another yeast prion called [PSI+]. Remarkably, we found that the [RNQ+] variants require different, non-contiguous regions of the Rnq1 protein for both prion propagation and [PSI+] induction. This included regions outside of the canonical prion-forming domain of Rnq1. Remarkably, such differences did not result in variation in aggregate stability. Our analysis also revealed a striking difference in the ability of these [RNQ+] variants to interact with the chaperone Sis1. Thus, our work shows that the differential influence of various amyloidogenic regions and interactions with host cofactors are critical determinants of the phenotypic consequences of distinct aggregate structures. This helps reveal the complex interdependent factors that influence how a particular amyloid structure may dictate disease pathology and progression. Protein conformational disorders, including many neurodegenerative diseases, result when a protein misfolds and undergoes a conformational change to form self-templating aggregates, called amyloid. Interestingly, the proteins that misfold in these diseases tend to form a wide variety of distinct aggregate structures. In prion diseases, these different amyloid conformations are called prion strains. The different conformations of prion strains are responsible for modulating disease progression, pathology, and transmission. Previous work with yeast prions has provided tremendous insight into how distinct prion conformers can cause such phenotypic variability. Here, we used a set of [RNQ+] prion variants to show the complex web of interactions involved in the propagation of distinct aggregate structures. We found that several different non-adjacent regions of Rnq1, even outside the prion-forming domain, make varying contributions to the propagation of distinct variants of the [RNQ+] prion. Moreover, our data support the hypothesis that the [RNQ+] variants differentially interact with the molecular chaperone Sis1. These data strongly suggest that the variable phenotypic manifestations of different aggregate conformations depend upon a unique set of primary structural elements and differential interactions with host cofactors.
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