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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Effects of Q/N-rich, polyQ, and non-polyQ amyloids on the de novo formation of the (PSI+) prion in yeast and aggregation of Sup35 in vitro.
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Effects of Q/N-rich, polyQ, and non-polyQ amyloids on the de novo formation of the (PSI+) prion in yeast and aggregation of Sup35 in vitro.

机译：富含Q / N，polyQ和non-polyQ淀粉样蛋白对酵母中（PSI +）ion病毒从头形成和Sup35聚集的影响。

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摘要

Prions are infectious protein conformations that are generally ordered protein aggregates. In the absence of prions, newly synthesized molecules of these same proteins usually maintain a conventional soluble conformation. However, prions occasionally arise even without a homologous prion template. The conformational switch that results in the de novo appearance of yeast prions with glutamine/aspargine (Q/N)-rich prion domains (e.g., [PSI+]), is promoted by heterologous prions with a similar domain (e.g., [RNQ+], also known as [PIN+]), or by overexpression of proteins with prion-like Q-, N-, or Q/N-rich domains. This finding led to the hypothesis that aggregates of heterologous proteins provide an imperfect template on which the new prion is seeded. Indeed, we show that newly forming Sup35 and preexisting Rnq1 aggregates always colocalize when [PSI+] appearance is facilitated by the [RNQ+] prion, and that Rnq1 fibers enhance the in vitro formation of fibers by the prion domain of Sup35 (NM). The proteins do not however form mixed, interdigitated aggregates. We also demonstrate that aggregating variants of the polyQ-containing domain of huntingtin promote the de novo conversion of Sup35 into [PSI+]; whereas nonaggregating variants of huntingtin and aggregates of non-polyQ amyloidogenic proteins, transthyretin, alpha-synuclein, and synphilin do not. Furthermore, transthyretin and alpha-synuclein amyloids do not facilitate NM aggregation in vitro, even though in [PSI+] cells NM and transthyretin aggregates also occasionally colocalize. Our data, especially the in vitro reproduction of the highly specific heterologous seeding effect, provide strong support for the hypothesis of cross-seeding in the spontaneous initiation of prion states.
机译：ions病毒是传染性蛋白质构象，通常是有序的蛋白质聚集体。在没有病毒的情况下，这些相同蛋白质的新合成分子通常保持常规的可溶性构象。但是，即使没有同源病毒模板，有时也会出现病毒。带有富含谷氨酰胺/天冬氨酸（Q / N）pr病毒结构域（例如[PSI +]）的酵母病毒从头出现的构象转换，是由具有相似结构域（例如[RNQ +]，也称为[PIN +]），或通过富含病毒的Q-，N-或Q / N富集结构域的蛋白质过表达。这一发现导致了这样一个假设，即异源蛋白质的聚集体提供了一个不完美的模板，新的ion病毒被植入了该模板。确实，我们显示，当[RNQ +] ion病毒促进[PSI +]出现时，新形成的Sup35和预先存在的Rnq1聚集体始终共定位，并且Rnq1纤维通过Sup35（NM）的ion病毒域增强了纤维的体外形成。但是，蛋白质不会形成混合的，相互交叉的聚集体。我们还证明，亨廷顿蛋白的含有polyQ的域的聚集变体可以促进Sup35从头转化为[PSI +]。而亨廷顿蛋白的非聚集变体和非polyQ淀粉样蛋白，运甲状腺素蛋白，α-突触核蛋白和亲核蛋白的聚集体则没有。此外，运甲状腺素蛋白和α-突触核蛋白淀粉样蛋白在体外不促进NM聚集，即使在[PSI +]细胞中NM和运甲状腺素蛋白聚集也偶尔共定位。我们的数据，特别是高度特异异种接种效应的体外复制，为for病毒状态自发引发的交叉播种假说提供了有力的支持。

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