Prion-mediated protein aggregation/co-aggregation and cellular consequence

朊病毒疾病，也称为传染性海绵状脑病（TSE）， 属于哺乳动物蛋白质错误折叠神经变性疾病的亚组。的 导致TSE的病原体是一组错误折叠的构象异构体（PrPSc）， 其他正常细胞蛋白（PrPC）。这种构象的潜在机制 转变还不明确，TSE目前仍然是毁灭性和不可治愈的。有趣的是， 朊病毒或朊病毒样蛋白已经在广泛的真核和原核生物中被鉴定 生物，不仅在疾病病理学中，而且在正常生物学中发挥重要作用， 功能协调发展的这些易于聚集的蛋白质在形成自我维持的 可以在细胞之间或组织之间传递的构象（通常是淀粉样蛋白）。 然而，我们仍处于阐明淀粉样蛋白介导的机制的早期阶段， 导致不同的细胞表型和病理。在芽殖酵母中， 在酿酒酵母中，至少有八种朊病毒蛋白已被证实，这已被证明是有价值的 研究朊病毒生物学的模型。例如，在我们的研究中发现的Swi 1朊病毒（[SWI+]） 实验室通常是ATP依赖性染色质重塑复合物SWI/SNF的亚基， 并且是第一个被证明参与酵母大规模转录调节的朊病毒。于 构象开关，携带[SWI+]朊病毒的细胞显示出在使用 非葡萄糖碳源和多细胞特征的完全丧失。但 [SWI+]的结构决定因素及其在朊病毒介导的细胞行为中的作用仍然是 难以捉摸。此外，积累的证据表明，不同的酵母朊病毒可能相互作用， 协调一致地调节重要的细胞特征，例如酵母二型性-在 单细胞形式和多细胞形式，涉及丰富的蛋白质相互作用事件，如 共聚合。因此，在本项目中，我们建议描述序列特征 Swi 1的（残基）对于Swi 1淀粉样蛋白形成、[SWI+]形成和 传播我们还计划研究Swi 1朊病毒如何与其他朊病毒相互作用，如 Mot 3（[MOT 3 +]）和/或Cyc 8（[OCT+]）朊病毒调节酵母多细胞性和全局基因 转录响应于细胞和环境条件。最后，我们计划确定 朊病毒相互作用的蛋白质和细胞机制，并检查这种意义 淀粉样蛋白生成和朊病毒传播的相互作用。这个项目的成功 淀粉样蛋白形成蛋白的结构，以及蛋白质的调控机制 淀粉样蛋白生成、朊病毒传播和蛋白质相互作用，这些都与朊病毒密切相关， 介导的细胞表型和人类蛋白质错误折叠疾病， 疾病（AD）。

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), belong to a subgroup of mammalian protein-misfolding neurodegenerative disorders. The pathogens responsible for TSEs are a collection of misfolded conformers (PrPSc) of an otherwise normal cellular protein (PrPC). The mechanism underlying such a conformational switch is yet ambiguous, and TSEs currently remain devastating and incurable. Intriguingly, prion or prion-like proteins have been identified in a broad range of eukaryotic and prokaryotic organisms, playing important roles in not only disease pathologies but also normal biological functions. These aggregation-prone proteins are common in forming self-sustaining conformations (usually amyloids) that can be transmitted from cell to cell, or tissue to tissue. However, we are still in an early stage in elucidating the amyloid-mediated mechanisms that contribute to diverse cellular phenotypes and pathologies. In the budding yeast Saccharomyces cerevisiae, at least eight prion proteins have been verified, which have been proven valuable models for studying prion biology. For example, the Swi1 prion ([SWI+]) discovered in our laboratory is normally a subunit of the ATP-dependent chromatin-remodeling complex SWI/SNF, and is the first prion shown to involve in massive transcriptional regulation of yeast. Upon the conformational switch, cells carrying the [SWI+] prion show a compromised capacity in using non-glucose carbon sources and a complete loss of multicellular features. However, the structural determinants of [SWI+] and their roles in prion-mediated cellular behaviors are still elusive. Moreover, accumulated evidence suggests that distinct yeast prions may interact and act in concert to regulate important cellular traits such as yeast dimorphism – switching between a unicellular form and multicellular forms, involving abundant protein interaction events such as co-aggregation. Thus, in this project, we propose to characterize the sequence features (residues) of Swi1 that are essential for Swi1 amyloid formation, [SWI+] formation and propagation. We also plan to investigate how the Swi1 prion interacts with other prions, such as Mot3 ([MOT3+]) and/or Cyc8 ([OCT+]) prions to regulate yeast multicellularity and global gene transcription in response to cellular and environmental conditions. Finally, we plan to identify prion-interacting proteins and cellular machineries, and examine the significance of such interactions in amyloidogenesis and prion transmission. The success of this project will shed light on the structure of amyloid-forming proteins, and the mechanism governing protein amyloidogenesis, prion transmission, and protein interactions, which are tightly linked to prion- mediated cellular phenotypes and human protein misfolding diseases such as Alzheimer's diseases (AD).