Amyloid aggregation and prion formation in bacteria
细菌中淀粉样蛋白聚集和朊病毒形成
基本信息
- 批准号:9551739
- 负责人:
- 金额:$ 1.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-13 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptedAlgorithmsAlpha CellAmyloidBacteriaBacterial ProteinsBiological AssayBiologyCell SurvivalCell physiologyCellsCytoplasmData SetDeltastabEpigenetic ProcessEscherichia coliFoundationsGoalsGrowthHeredityHeritabilityHumanInfectious AgentInvestigationLibrariesLifeMammalsMethodsModelingMolecular ChaperonesMolecular MachinesNeurodegenerative DisordersOrthologous GenePhenotypePrPPrion DiseasesPrionsProteinsResearchRoleSaccharomycetalesSourceStressStructureTimeTrainingTransplantationValidationYeast Model SystemYeastsamyloid fibril formationamyloidogenesisbasechaperone machineryconformational conversiondesignexperimental studyfitnessfungusgenetic elementloss of functionmarkov modelpermissivenesspolypeptideprion hypothesisprion-likeprotein aggregatepublic health relevancetooltool developmentvirtualyeast prion
项目摘要
DESCRIPTION (provided by applicant): Prions are infectious, self-propagating protein aggregates that were first described in the context of a group of fatal neurodegenerative diseases known as the transmissible spongiform encephalopathies (TSEs), which afflict humans and other mammals. The protein culprit in the case of the TSEs is an endogenous protein called PrP that has an inherent ability to undergo a dramatic conformational conversion, leading to the formation of distinctive cross-β aggregates (termed amyloid) that are both self-templating and infectious. Prions have also been uncovered in budding yeast and other fungi, where they act as protein-based genetic elements that confer new phenotypes on those cells that harbor them. Like PrP, fungal prion proteins exist in either a native, soluble form or a self-perpetuating, amyloid form (the prion form) that is infectious. Involved in diverse cellular processes, fungal prion proteins can, in their prion forms, enhance cell survival under specific stress conditions. Although prion proteins are widely distributed throughout the fungal kingdom, it is not yet known if they exist in the bacterial domain of life. The foundation for the proposed research is our recent demonstration that E. coli cells can propagate a model yeast prion in a manner that depends on the activity of a conserved cellular chaperone assembly that is also required for prion propagation in yeast. These findings indicate that the basic requirements for protein-based heredity are satisfied in the bacterial domain of life, suggesting that prion-like phenomena may predate the evolutionary split between bacteria and yeast. The proposed research will address this hypothesis through the development of tools and approaches for uncovering prion-like proteins in bacteria, while at the same time investigating the determinants that dictate protein amyloidogenicity. In aim 1, we will systematically investigate the chaperone requirements for prion propagation in E. coli. In aim 2, we will screen bacterially encoded polypeptides for amyloidogenicity, as a means to identify candidate prion-like proteins and also to generate an unbiased experimental data set for evaluating the steric zipper model for protein amyloidogenicity. In aim 3, we will develop and implement a complementary set of approaches to detect prion-like phenomena in bacteria. Together, the proposed experiments will enable a deeper understanding of the cellular requirements for prion formation and propagation, will help elucidate the intrinsic determinants of protein amyloidogenicity and will facilitate the discovery f new protein-based epigenetic sources of phenotypic diversity in the bacterial domain of life.
描述(由申请人提供):朊病毒是感染性的、自繁殖的蛋白质聚集体,其首先在一组称为传染性海绵状脑病(TSE)的致死性神经变性疾病的背景下被描述,其折磨人类和其他哺乳动物。在TSE的情况下,蛋白质罪魁祸首是一种称为PrP的内源性蛋白质,其具有进行剧烈构象转换的固有能力,导致形成独特的交叉β聚集体(称为淀粉样蛋白),其既具有自模板性又具有感染性。在芽殖酵母和其他真菌中也发现了朊病毒,它们作为基于蛋白质的遗传元件,赋予那些携带它们的细胞新的表型。像PrP一样,真菌朊病毒蛋白以天然的可溶性形式或具有感染性的自我永存的淀粉样蛋白形式(朊病毒形式)存在。真菌朊病毒蛋白参与多种细胞过程,以朊病毒的形式,可以增强细胞在特定应激条件下的存活。虽然朊病毒蛋白广泛分布在真菌王国,但尚不清楚它们是否存在于细菌的生命领域。这项研究的基础是我们最近证明了E.大肠杆菌细胞可以以依赖于保守的细胞伴侣组装体的活性的方式繁殖模型酵母朊病毒,所述保守的细胞伴侣组装体也是朊病毒在酵母中繁殖所需的。这些发现表明,基于蛋白质的遗传的基本要求在细菌生命领域得到满足,这表明朊病毒样现象可能早于细菌和酵母之间的进化分裂。拟议的研究将通过开发用于揭示细菌中朊病毒样蛋白的工具和方法来解决这一假设,同时调查决定蛋白质淀粉样蛋白的决定因素。在目的1中,我们将系统地研究朊病毒在E.杆菌在目标2中,我们将筛选细菌编码的多肽的淀粉样变性,作为一种手段,以确定候选朊病毒样蛋白,并产生一个公正的实验数据集,用于评估蛋白质淀粉样变性的空间拉链模型。在目标3中,我们将开发和实施一套互补的方法来检测细菌中的朊病毒样现象。总之,拟议的实验将使更深入地了解朊病毒的形成和繁殖的细胞要求,将有助于阐明蛋白质淀粉样变性的内在决定因素,并将促进发现新的蛋白质为基础的表观遗传来源的表型多样性的细菌生活领域。
项目成果
期刊论文数量(0)
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Ann Hochschild其他文献
Ann Hochschild的其他文献
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{{ truncateString('Ann Hochschild', 18)}}的其他基金
Amyloid aggregation and prion formation in bacteria
细菌中淀粉样蛋白聚集和朊病毒形成
- 批准号:
9102529 - 财政年份:2016
- 资助金额:
$ 1.59万 - 项目类别:
A new genetic approach for studying prions and other pathogenic protein aggregate
研究朊病毒和其他致病蛋白聚集体的新遗传学方法
- 批准号:
8137722 - 财政年份:2008
- 资助金额:
$ 1.59万 - 项目类别:
A new genetic approach for studying prions and other pathogenic protein aggregate
研究朊病毒和其他致病蛋白聚集体的新遗传学方法
- 批准号:
7691337 - 财政年份:2008
- 资助金额:
$ 1.59万 - 项目类别:
A new genetic approach for studying prions and other pathogenic protein aggregate
研究朊病毒和其他致病蛋白聚集体的新遗传学方法
- 批准号:
7906889 - 财政年份:2008
- 资助金额:
$ 1.59万 - 项目类别:
A new genetic approach for studying prions and other pathogenic protein aggregate
研究朊病毒和其他致病蛋白聚集体的新遗传学方法
- 批准号:
8306136 - 财政年份:2008
- 资助金额:
$ 1.59万 - 项目类别:
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