A PRION REVEALS COMPLEX TRAITS AND PHENOTYPIC DIVERSITY

朊病毒揭示了复杂的特征和表型多样性

• 批准号: 8460929
• 负责人: HEATHER L TRUE-KROB
• 金额: $ 34.47万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460929
• 关键词: Adopted; Alzheimer' s Disease; Amyloid; Area; Attention; Biology; Cell Cycle Progression; Cell Death; Cell physiology; Cells; Complex; Cytoplasm; Data; Development; Disease; Elements; Employee Strikes; Environment; Epigenetic Process; Event; Evolution; Fiber; Funding; Gene Expression Regulation; Genetic; Goals; Huntington Disease; Inherited; Investigation; Lead; Life; Malignant Neoplasms; Mediating; Metabolic; Molecular Conformation; Mothers; Nature; Neurodegenerative Disorders; Nutrient; Organism; Parkinson Disease; Phenotype; Post-Translational Protein Processing; PrP; Prion Diseases; Prions; Process; Protein Structure Initiative; Proteins; Regulation; Reporter; Research; Saccharomyces cerevisiae; Saccharomycetales; Signal Transduction; Stress; Structure; System; Translations; Variant; Virus; Work; Yeasts; base; cell growth; daughter cell; environmental change; gain of function; human disease; interest; loss of function; non-genetic; non-prion; novel; overexpression; pathogen; polymerization; premature; prion hypothesis; protein aggregate; protein expression; protein function; protein misfolding; protein structure; protein structure function; response; sup35; termination factor; trait; transmission process; yeast prion

DESCRIPTION (provided by applicant): Proteins must adopt the correct folded structure for full functionality. For some proteins, post-translational modifications have a tremendous impact on both the structure and the function of the protein. Structural regulatory control of protein function has been well- established in many facets of biology and is often a key control step in signal transduction events that are essential for life, such as the response to nutrients and stresses, cell cycle progression, and proliferation. However, unexpected alterations in protein structure can be detrimental. Misfolded proteins are frequently associated with irreversible loss-of-function and disease instead of regulation. Protein misfolding and aberrant polymerization have been implicated in many neurodegenerative disorders including Parkinson's, Alzheimer's, Huntington's, and prion diseases. We are investigating how a group of proteins adopt a specific type of "misfolded" state (prion conformation) as a regulatory mechanism. These proteins may have evolved with the intrinsic ability to produce major changes in conformation as a means of regulation. This mechanism (prion propagation) provides an epigenetic switch that is self-perpetuating and is transmitted from mother cells to their daughter cells when the prion protein is transmitted through the cytoplasm. Due to their unique mode of propagation and inheritance, these prions have a profound impact on the ability of the organism to alter its phenotypes and adapt to changing environments. These prion proteins may represent remnants of an ancient regulatory mechanism that is still maintained in the budding yeast Saccharomyces cerevisiae. We now have evidence to suggest that phenotypic adaptation can be regulated by a network of prion proteins in yeast. Elucidating the underlying mechanistic principles of this epigenetic mechanism of regulation is a key first step in revealing the global impact of this type of regulation on protein expression to alter phenotypes, adaptation, and survival.

描述（由申请方提供）：蛋白质必须采用正确的折叠结构才能实现完整功能。对于一些蛋白质，翻译后修饰对蛋白质的结构和功能都有巨大的影响。蛋白质功能的结构调节控制在生物学的许多方面已经得到了很好的建立，并且通常是生命所必需的信号转导事件中的关键控制步骤，例如对营养物和应激的响应、细胞周期进展和增殖。然而，蛋白质结构的意外改变可能是有害的。错误折叠的蛋白质通常与不可逆的功能丧失和疾病有关，而不是调节。蛋白质错误折叠和异常聚合已经涉及许多神经退行性疾病，包括帕金森病、阿尔茨海默病、亨廷顿病和朊病毒疾病。我们正在研究一组蛋白质如何采用一种特定类型的“错误折叠”状态（朊病毒构象）作为调节机制。这些蛋白质可能已经进化出内在的能力，产生构象的主要变化作为一种调控手段。这种机制（朊病毒传播）提供了一个表观遗传开关，它是自我延续的，当朊病毒蛋白通过细胞质传递时，它从母细胞传递到其子细胞。由于它们独特的繁殖和遗传模式，这些朊病毒对生物体改变其表型和适应不断变化的环境的能力具有深远的影响。这些朊病毒蛋白可能代表了古老调节机制的残余，该机制仍然保留在萌芽酵母酿酒酵母中。我们现在有证据表明，表型适应可以通过酵母中的朊病毒蛋白网络来调节。阐明这种表观遗传调控机制的基本机制原则是揭示这种类型的调控对蛋白质表达的全球影响以改变表型，适应和生存的关键第一步。