Nucleic Acids Roles in Protein Folding and Aggregation

项目总结 该项目旨在研究核酸是如何参与蛋白质聚集和折叠的。蛋白 错误折叠和聚集会导致许多衰弱的疾病，包括阿尔茨海默病。我们最近 发现核酸可以具有很强的伴侣活性，以防止蛋白质聚集和帮助蛋白质 折叠。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，它是高度 很可能核酸是蛋白质动态平衡的重要参与者。这份建议书中描述的工作奠定了 为我们提供对核酸调节蛋白质的基本原理的第一次了解 折叠和聚集，从而实现蛋白质的动态平衡。 我们目前的调查旨在解决两个关键方面：1)了解 2)了解分子伴侣核的分子机制 酸。这些研究采用跨学科的方法，结合了分子生物学、生物化学、 生物物理学和细菌遗传学。 我们的初步数据表明，核酸防止和促进齐聚的活性 高度依赖于序列，并且特别由四链结构编码。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。这一洞察力也给了我们 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。我们的 初步数据还表明，含有四链的伴侣序列在 改善大肠杆菌中的折叠环境。我们目前正在将这些研究扩展到已知的四联体 细胞内具有伴侣样效应的结构，并研究伴侣活性的结构基础。 总之，这些研究将为对蛋白质动态平衡的新理解以及它是如何 与核酸生物学有关。这些信息在未来将是帮助对抗无数蛋白质的关键 错误折叠和聚集性疾病。

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.