Soluble oligomers are sufficient for transmission of a yeast prion but do not confer phenotype.
Soluble oligomers are sufficient for transmission of a yeast prion but do not confer phenotype.
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DOI：
10.1083/jcb.201307040
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发表时间：
2013-10-28
期刊：
影响因子：
--
通讯作者：
True HL
中科院分区：
文献类型：
--
作者：
Dulle JE;Bouttenot RE;Underwood LA;True HL
朊病毒表型需要大的、不溶性的酵母朊病毒蛋白聚集体，但可溶性寡聚体包含传递朊病毒构象所需的所有信息。淀粉样蛋白通过自模板机制聚集，该机制可能涉及寡聚体或前原纤维中间体。对于疾病相关的淀粉样蛋白，这些中间体被认为是细胞毒性的主要原因。然而，这些低聚中间体的分离和表征已被证明是困难的，引发了关于其在疾病病理学中的生物学相关性的争议。在这里，我们描述了一个寡聚物种的酵母朊病毒蛋白在细胞中，是足够的朊病毒传播和感染性。这些寡聚体与经典朊病毒聚集体的不同之处在于它们是可溶的并且对SDS的抗性较低。我们发现，大的，SDS-抗性聚集体所需的朊病毒表型，但可溶性的，更SDS敏感的寡聚体包含所有必要的信息传递朊病毒构象。因此，我们确定了两种类型的朊病毒物种的内源性表观遗传元件的不同功能的要求。此外，酵母朊病毒蛋白质的无毒的、自我复制的淀粉样蛋白构象体再次为淀粉样蛋白在细胞中形成和繁殖的机制提供了有价值的见解。
Large, insoluble aggregates of a yeast prion protein are required for the prion phenotype, but soluble oligomers contain all the information necessary to transmit the prion conformation. Amyloidogenic proteins aggregate through a self-templating mechanism that likely involves oligomeric or prefibrillar intermediates. For disease-associated amyloidogenic proteins, such intermediates have been suggested to be the primary cause of cellular toxicity. However, isolation and characterization of these oligomeric intermediates has proven difficult, sparking controversy over their biological relevance in disease pathology. Here, we describe an oligomeric species of a yeast prion protein in cells that is sufficient for prion transmission and infectivity. These oligomers differ from the classic prion aggregates in that they are soluble and less resistant to SDS. We found that large, SDS-resistant aggregates were required for the prion phenotype but that soluble, more SDS-sensitive oligomers contained all the information necessary to transmit the prion conformation. Thus, we identified distinct functional requirements of two types of prion species for this endogenous epigenetic element. Furthermore, the nontoxic, self-replicating amyloid conformers of yeast prion proteins have again provided valuable insight into the mechanisms of amyloid formation and propagation in cells.
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