Nucleation seed size determines amyloid clearance and establishes a barrier to prion appearance in yeast.
Nucleation seed size determines amyloid clearance and establishes a barrier to prion appearance in yeast.
复制标题
成核种子大小决定了淀粉样蛋白的清除率，并为酵母中朊病毒的出现建立了屏障。
DOI：
10.1038/s41594-020-0416-6
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发表时间：
2020
影响因子：
16.8
通讯作者：
Serio,TriciaR
中科院分区：
文献类型：
--
作者：
Villali,Janice;Dark,Jason;Brechtel,TealM;Pei,Fen;Sindi,SuzanneS;Serio,TriciaR
淀粉样蛋白的出现是一种罕见的事件，在其他聚集蛋白的存在下促进。这些聚集体被认为是通过模板的组装成核种子的形成，但我们发现一个意想不到的作用，他们在增强淀粉样蛋白的持久性后，它的出现。具体而言，SaccharomycesParaeRnq1淀粉样蛋白减少了分子伴侣介导的Sup35淀粉样蛋白的分解，促进了其在酵母中的持久性。数学建模和相应的体内实验将淀粉样蛋白持久性与Sup35成核种子的构象定义的大小联系起来，并表明淀粉样蛋白通过低于此阈值的分解而被主动清除，以抑制[PSI+]朊病毒在体内的出现。值得注意的是，这个框架解决了酵母朊病毒的外观和固化中的多个已知的不一致性。因此，我们的观察结果建立了核种子的大小作为一个以前不受重视的特性的朊病毒变体，这是关键，以了解朊病毒状态之间的转换。
Amyloid appearance is a rare event that is promoted in the presence of other aggregated proteins. These aggregates were thought to act by templating the formation of an assembly-competent nucleation seed, but we find an unanticipated role for them in enhancing the persistence of amyloid after it arises. Specifically,Saccharomyces cerevisiaeRnq1 amyloid reduces chaperone-mediated disassembly of Sup35 amyloid, promoting its persistence in yeast. Mathematical modeling and corresponding in vivo experiments link amyloid persistence to the conformationally defined size of the Sup35 nucleation seed and suggest that amyloid is actively cleared by disassembly below this threshold to suppress appearance of the [PSI+] prion in vivo. Remarkably, this framework resolves multiple known inconsistencies in the appearance and curing of yeast prions. Thus, our observations establish the size of the nucleation seed as a previously unappreciated characteristic of prion variants that is key to understanding transitions between prion states.