Nucleic Acids Roles in Protein Folding and Aggregation

项目摘要 本计画旨在探讨核酸如何参与蛋白质的聚集与折叠。蛋白 错误折叠和聚集导致许多使人衰弱的疾病，包括阿尔茨海默病。我们最近 发现核酸可以具有强的伴侣活性，以防止蛋白质聚集并帮助蛋白质 折页.鉴于它们在细胞中的优势以及对蛋白质折叠和聚集的强烈影响， 很可能核酸是蛋白质稳态的重要参与者。本提案中所述的工作 我们的研究提供了我们对核酸调节蛋白质的基本原理的第一次理解 折叠和聚集，从而蛋白质稳态。 我们目前的调查是针对解决两个关键方面：1）了解的作用， 分子伴侣核酸在细胞中，和2）了解分子伴侣核酸的分子机制 acids.这些研究利用了分子生物学、生物化学、 生物物理学和细菌遗传学。 我们的初步数据表明，核酸阻止和促进寡聚化的活性 是高度序列依赖性的，尤其是由四链体结构编码。这些结果有助于 解释几种神经退行性疾病的生物物理原因。这种洞察力也给了我们 利用特定的核酸序列和结构控制和研究蛋白质聚集的机会。我们 初步数据还表明，含有四链体的伴侣蛋白序列在 改善了E.杆菌我们目前正在将这些研究扩展到已知的四倍体 在细胞中具有伴侣样作用的结构，并研究伴侣活性的结构基础。 总之，这些研究将为蛋白质稳态的新理解奠定基础，以及它是如何 涉及核酸生物学。这一信息在未来将是至关重要的，以帮助打击无数的蛋白质 错误折叠和聚集疾病。

PROJECT SUMMARY This project is to investigate how nucleic acids are involved in protein aggregation and folding. Protein misfolding and aggregation lead to many debilitating diseases including Alzheimer’s disease. We recently found that nucleic acids can have strong chaperone activity to prevent protein aggregation and aid protein folding. Given their preponderance in the cell and strong effects on protein folding and aggregation, it is highly likely that nucleic acids are important players in protein homeostasis. The work described in this proposal lays out studies to provide our first understanding of the basic principles by which nucleic acids modulate protein folding and aggregation, and thus protein homeostasis. Our current investigations are directed at addressing two critical aspects: 1) Understanding the roles of chaperone nucleic acids in the cell, and 2) Understanding the molecular mechanism of chaperone nucleic acids. These studies utilize an interdisciplinary approach combining molecular biology, biochemistry, biophysics, and bacterial genetics. Our preliminary data indicates that both the activities of nucleic acids to prevent and promote oligomerization are highly sequence dependent, and are especially encoded for by quadruplex structures. These results help explain the biophysical causes of several neurodegenerative diseases. This insight also gives us the opportunity to control and study protein aggregation using specific nucleic acid sequences and structures. Our preliminary data also indicates that quadruplex-containing chaperone sequences are also effective at improving the folding environment in E. coli. We are currently expanding these studies to known quadruplex structures with chaperone-like effects in the cell, and investigating the structural basis of chaperone activity. Together, these studies will lay the foundation for a new understanding of protein homeostasis and how it relates to nucleic acid biology. This information will be critical in the future to help combat myriad protein misfolding and aggregation diseases.