A PRION REVEALS COMPLEX TRAITS AND PHENOTYPIC DIVERSITY

描述（由申请人提供）：蛋白质必须采用正确的折叠结构才能发挥全部功能。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控控制已经在生物学的许多方面得到了很好的确立，并且通常是对生命至关重要的信号转导事件的关键控制步骤，例如对营养和应激的反应，细胞周期的进展和增殖。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相关，而不是调节。蛋白质错误折叠和异常聚合与许多神经退行性疾病有关，包括帕金森氏症、阿尔茨海默氏症、亨廷顿氏症和朊病毒疾病。我们正在研究一组蛋白质如何采用特定类型的“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了内在的能力，可以产生重大的构象变化，作为一种调节手段。这种机制（朊病毒繁殖）提供了一种自我延续的表观遗传开关，当朊病毒蛋白通过细胞质传播时，它从母细胞传播到子细胞。由于其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一种古老的调控机制的残余，这种机制仍然维持在萌芽的酿酒酵母中。我们现在有证据表明表型适应可以由酵母中的朊病毒蛋白网络调节。阐明这种表观遗传调节机制的潜在机制原理是揭示这种调节对蛋白质表达的全球影响以改变表型、适应和生存的关键的第一步。

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.