Cellular Mechanisms and Consequences of Protein Misfolding and Resolution

8.项目摘要/摘要 许多蛋白质除了它们的天然状态外，还可以通过另一种途径进行折叠引导 淀粉样蛋白聚集体的形成。淀粉样蛋白的发生不仅与 人类的50种疾病，还包括有益于机体的功能。一旦出现， 淀粉样蛋白状态是通过掺入和构象转换天然- 状态蛋白、正在生长的复合体的碎片化以及在内部和向其他 个人。这些中心事件受蛋白质序列和构象、蛋白质 质量控制途径和细胞生物学。然而，这些促成因素和过程是如何 尽管越来越多的人意识到交叉点对生物体生理学的影响，但人们对此知之甚少 淀粉样蛋白对从酵母到人类的系统生物学的贡献。这一目前的差距 知识是在这一领域取得进展的关键障碍，因为我们无法理性地 解释、预测、开发和逆转淀粉样蛋白发生与其生理功能之间的联系 效果。我们的长期目标是通过确定如何平衡这些投入来弥合这一差距 并被破坏以创造和治愈动态表型状态。为此，我们正在利用 酿酒酵母中的普里安是一个杰出而稳健的模型。共享多个 后生动物淀粉样蛋白的特征，酵母蛋白是一个自然进化的系统，在其中 可以在下面访问、研究和遍历区分表型状态的阈值 生理上相关的条件。我们将利用酵母Pron生物学中的二分法，在那里 同一事件在不同的背景下产生不同的结果，作为实验入口 阐明最关键的转变的系统平衡：Pron的出现，干扰，治疗， 和毒性。总之，我们的研究将阐明蛋白质平衡生态位的分子基础 允许淀粉样蛋白存活或丢失，并将为理解类似的 高等真核生物的转变。

8. Project Summary/Abstract Many proteins access, in addition to their native state, an alternative pathway of folding leading to the formation of amyloid aggregates. Amyloidogenesis has been linked not only to more than fifty human diseases but also to functions, which benefit the organism. Once arising, the amyloid state is perpetuated through the incorporation and conformational conversion of native- state protein, fragmentation of growing complexes and transmission both within and to other individuals. These central events are modulated by protein sequence and conformation, protein quality control pathways, and cell biology. Yet, how these contributing factors and processes intersect to impact organismal physiology is poorly understood, despite a growing appreciation of the contributions of amyloid to the biology of systems from yeast to man. This current gap in knowledge is a critical barrier to progress in the field because we are unable to rationally explain, predict, exploit, and reverse the link between amyloidogenesis and its physiological effects. Our long-term goal is to bridge this gap by determining how these inputs are balanced and disrupted to create and cure dynamic phenotypic states. Toward this end, we are exploiting prions of Saccharomyces cerevisiae as an outstanding and robust model. Sharing many characteristics with metazoan amyloids, yeast prions are a naturally evolved system in which the thresholds separating phenotypic states can be accessed, studied, and traversed under physiologically relevant conditions. We will exploit dichotomies in yeast prion biology, where the same event yields distinct outcomes in different contexts, as experimental entryways to elucidate system balance for the most crucial transitions: prion appearance, interference, curing, and toxicity. Together, our studies will elucidate the molecular basis of proteostatic niches that allow amyloid to survive or to be lost and will provide a framework for understanding similar transitions in higher eukaryotes.