Cellular Mechanisms and Consequences of Protein Misfolding and Resolution

8.项目概要/摘要 许多蛋白质除了其天然状态外，还可以通过另一种折叠途径引导 淀粉样蛋白聚集体的形成。淀粉样蛋白生成不仅与 50种人类疾病，但也有功能，这有利于有机体。一旦出现， 淀粉样蛋白状态是通过天然蛋白的掺入和构象转化而永久存在的， 状态的蛋白质，不断增长的复合物的碎片化和传输内和其他 个体这些中心事件是由蛋白质序列和构象，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 尽管越来越多人认识到， 淀粉样蛋白对从酵母到人类的系统生物学的贡献。 知识是该领域进步的关键障碍，因为我们无法理性地 解释，预测，利用和逆转淀粉样蛋白生成及其生理学之间的联系 方面的影响.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 并被破坏以产生和治愈动态表型状态。为此，我们正在利用 朊病毒的酿酒酵母作为一个杰出的和强大的模型。分享许多 与后生动物淀粉样蛋白的特征一样，酵母朊病毒是一种自然进化的系统， 分离表型状态的阈值可以被访问、研究和遍历， 生理相关条件。我们将利用酵母朊病毒生物学中的二分法， 同一事件在不同的背景下产生不同的结果，作为实验性的入口， 阐明系统平衡的最关键的过渡：朊病毒的外观，干扰，治疗， 和毒性。总之，我们的研究将阐明蛋白质稳定小生境的分子基础， 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.