Oligopeptide Repeats and Prion Propagation
寡肽重复和朊病毒传播
基本信息
- 批准号:8326781
- 负责人:
- 金额:$ 2.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-01 至 2014-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptedAffectAppearanceBerylliumBiological AssayCellsCharacteristicsClinicalComplexDevelopmentDiseaseDisease ProgressionElementsEnvironmentEventGoalsHuntington DiseaseIn VitroIndiumIndividualKnowledgeLeadLinkMaintenanceMammalsMolecular ChaperonesMolecular ConformationN-terminalNatureNeurodegenerative DisordersOligopeptidesPathway interactionsPhenotypePhysiologyPrion DiseasesPrionsProcessProtein Structure InitiativeProteinsReadingResearchRoleSaccharomyces cerevisiaeSeriesSystemTerminator CodonTestingThermodynamicsVariantWorkYeastsdaughter cellin vivoinsightnovel therapeuticsphysical propertyprotein aggregationprotein foldingprotein misfoldingsup35transmission process
项目摘要
DESCRIPTION (provided by applicant): The misfolding normal, cellular encoded proteins and their subsequent aggregation has emerged as a common mechanism underlying several neurodegenerative diseases in mammals, including Huntington's and the Transmissible Spongiform Encephalopathies (prion diseases). A key event in this process is the efficient amplification of misfolded form, which occurs when existing aggregates direct the conversion of normal protein to a like state. This autocatalytic misfolding in influenced by sequence elements within the implicated proteins, such as repeated elements that modulate both the appearance and persistence of the misfolded form. Despite their importance, the mechanism(s) by which these sequence elements influence the autocatalytic misfolding pathway is currently unknown. The goal of this proposal is to address this significant gap in knowledge. For this work, we will use the Sup35/[PSI+] prion system in the yeast S. cerevisiae. The Sup35 protein contains five and a half imperfect copies of an oligopeptide repeat. Deletion of one or more full repeats completely abolishes the autocatalytic misfolding of Sup35, while expansion of the repeat region increases the propensity of cells to adopt and propagate this form. We hypothesize that the oligopeptide repeats alter the efficiency of discrete steps in the Sup35 misfolding pathway and thereby the stability of the prion-associated phenotype by impacting the nature of Sup35 physical interactions. To test this hypothesis, we will identify the step(s) in the Sup35 autocatalytic misfolding pathway that are altered by variation in the number of repeats and impact of these variations on Sup35 interactions with itself and other cellular factors. By understanding how specific sequence elements modulate the protein folding environment in vivo, we will begin to understand how they contribute to both the normal cellular state and the corresponding disease state. Understanding how these sequence elements can modulate protein folding pathways within the context of the cellular environment will provide insight into how protein misfolding diseases are initiated and maintained.
描述(由申请人提供):正常的细胞编码蛋白的错误折叠及其随后的聚集已成为哺乳动物中几种神经退行性疾病的共同机制,包括亨廷顿舞蹈症和传染性海绵状脑病(朊病毒疾病)。这个过程中的一个关键事件是错误折叠形式的有效扩增,当现有的聚集体将正常蛋白质转化为类似状态时,就会发生这种情况。这种自催化错误折叠受到相关蛋白内序列元素的影响,例如调节错误折叠形式的外观和持久性的重复元素。尽管它们很重要,但这些序列元件影响自催化错误折叠途径的机制目前尚不清楚。本提案的目标是解决这一知识上的重大差距。在这项工作中,我们将在酿酒酵母中使用Sup35/[PSI+]朊病毒系统。Sup35蛋白包含五个半不完美的寡肽重复拷贝。删除一个或多个完整重复完全消除了Sup35的自催化错误折叠,而重复区域的扩增增加了细胞采用和繁殖这种形式的倾向。我们假设寡肽重复通过影响Sup35物理相互作用的性质,改变了Sup35错误折叠途径中离散步骤的效率,从而改变了朊病毒相关表型的稳定性。为了验证这一假设,我们将确定Sup35自催化错误折叠途径中的步骤,这些步骤会因重复次数的变化而改变,以及这些变化对Sup35自身和其他细胞因子相互作用的影响。通过了解特定序列元件如何在体内调节蛋白质折叠环境,我们将开始了解它们如何促进正常细胞状态和相应的疾病状态。了解这些序列元件如何在细胞环境中调节蛋白质折叠途径将有助于了解蛋白质错误折叠疾病是如何启动和维持的。
项目成果
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Christine Ricalo Langlois其他文献
Christine Ricalo Langlois的其他文献
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