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。对于一些蛋白质来说，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在生物学的许多方面都得到了很好的证实，并且往往是生命所必需的信号转导事件的关键控制步骤，如对营养和胁迫的反应、细胞周期进展和增殖。然而，蛋白质结构的意外变化可能是有害的。错误折叠的蛋白质经常与不可逆转的功能丧失和疾病有关，而不是与调节有关。蛋白质的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、亨廷顿氏症和普里恩病。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(Pron构象)作为一种调节机制。这些蛋白质可能进化出了内在的能力，作为一种调节手段，能够在构象上产生重大变化。这种机制(Prion繁殖)提供了一种表观遗传开关，这种开关是自我延续的，当Prion蛋白通过细胞质传递时，这种开关从母细胞传递到子细胞。由于它们独特的繁殖和遗传模式，这些普恩对生物体改变其表型和适应不断变化的环境的能力产生了深远的影响。这些蛋白可能代表了一种古老的调控机制的残留物，该机制仍然存在于萌芽中的酵母中。我们现在有证据表明，表型适应可以由酵母中的普恩蛋白网络来调节。阐明这种表观遗传调控机制的基本机制是揭示这种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。

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.