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

Pron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退行性疾病的一个亚群。这个 导致TSE的病原体是一组错误折叠的构象(PrPSc) 其他正常细胞蛋白(PrPC)。这种构象形成的机制 切换仍然是模棱两可的，TSE目前仍然是毁灭性的和不可治愈的。有趣的是， 在广泛的真核生物和原核生物中都发现了普恩或类似普恩的蛋白。 生物体，不仅在疾病病理学中发挥重要作用，而且在正常生物学中也发挥重要作用 功能。这些易于聚集的蛋白质在形成自我维持的过程中是常见的 可在细胞间或组织间传播的构象(通常为淀粉样蛋白)。 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。芽殖酵母中的酵母菌 在酿酒酵母中，至少有8种普里恩蛋白已被验证，并已被证明是有价值的 研究普里子生物学的模型。例如，在我们的 Lab通常是依赖于ATP的染色质重塑复合体SWI/SNF的一个亚单位， 而且是第一个被证明参与酵母大规模转录调控的病毒。在此之前 构象开关，携带[SWI]Prion的细胞在使用时显示出能力受损 非葡萄糖碳源和完全丧失多细胞功能。然而， [SWI]的结构决定因素及其在普恩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，不同的酵母蛋白可能相互作用并 协调行动来调节重要的细胞特征，如酵母二型--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 共同聚合。因此，在这个项目中，我们建议对序列特征进行表征 Swi1的(残基)对于Swi1淀粉样蛋白的形成、[SWI]的形成和 传播。我们还计划研究Swi1蛋白如何与其他蛋白相互作用，例如 Mot3([mot3])和/或Cyc8([oct])蛋白调节酵母多细胞性和全局性基因 转录对细胞和环境条件的反应。最后，我们计划确定 Prion相互作用的蛋白质和细胞机制，并检测这些 淀粉样蛋白发生和蛋白传递中的相互作用。这个项目的成功将有损于 淀粉样蛋白形成蛋白的结构和控制蛋白的机制 淀粉样蛋白的发生、普恩的传递和蛋白质的相互作用，这些都与普恩紧密相连。 介导的细胞表型与阿尔茨海默病等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).