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

朊病毒介导的蛋白质聚集/共聚集和细胞后果

基本信息

批准号：
10457851
负责人：
Zhiqiang Du
金额：
$ 31.73万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457851
关键词：
Alzheimer&apos s Disease Amyloid Animals Bacteria Biological Process Biology Biotin Carbon Cell physiology Cells Chromatin Remodeling Factor Collection Disease Elements Epigenetic Process Etiology Event Genetic Transcription Human In Vitro Isomerism Knowledge Label Laboratories Light Link Mass Spectrum Analysis Mediating Modeling Molecular Molecular Conformation Morphology Neurodegenerative Disorders Organism Pathogenicity Pathology Phenotype Physiological Plants Play PrP PrPSc Proteins Prion Diseases Prions Proteins Research Role Saccharomyces cerevisiae Saccharomycetales Source Stress Structure Study models Subgroup Switching Complex Testing Tissues Transcriptional Regulation Yeasts amyloid formation amyloid structure amyloidogenesis base cell behavior cell growth regulation conformer dimorphism fungus insight link protein neurotoxicity novel therapeutics pathogen prion-based prion-like protein aggregation protein misfolding response success trait transmission process yeast prion

项目摘要

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).

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的细胞在使用中表现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Pron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 (残基)对Swi1淀粉样蛋白形成、[SWI+]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)。