Nucleic Acids Roles in Protein Folding and Aggregation

核酸在蛋白质折叠和聚集中的作用

• 批准号: 10270767
• 负责人: Scott Andrew Horowitz
• 金额: $ 36.83万
• 依托单位: UNIVERSITY OF DENVER (COLORADO SEMINARY)
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10270767
• 关键词: Address; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Base Sequence; Biochemistry; Biology; Biophysics; Cells; DNA; Data; Disease; Environment; Escherichia coli; Foundations; Future; Investigation; Lead; Molecular; Molecular Biology; Molecular Chaperones; Neurodegenerative Disorders; Nucleic Acids; Parkinson Disease; Plant Roots; Play; Proteins; RNA; Research; Role; Structure; Work; activation-induced cytidine deaminase; bacterial genetics; base; combat; improved; insight; interdisciplinary approach; prevent; protein aggregation; protein folding; protein misfolding; proteostasis

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.

项目摘要 该项目是研究核酸如何参与蛋白质聚集和折叠。蛋白质 错误折叠和聚集导致许多令人衰弱的疾病，包括阿尔茨海默氏病。我们最近 发现核酸可以具有强大的伴侣活性，以防止蛋白质聚集和辅助蛋白 折叠式的。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，它是高度的 核酸可能是蛋白质稳态的重要参与者。该提案中描述的工作 淘汰我们对核酸调节蛋白质的基本原理的首次理解 折叠和聚集，从而蛋白质稳态。 我们目前的调查旨在解决两个关键方面：1）了解 细胞中的伴侣核酸和2）了解伴侣核酸的分子机制 酸。这些研究采用了跨学科方法，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，两种核酸的活性都可以预防和促进寡聚化 高度序列依赖性，特别是由四链体结构编码。这些结果有帮助 解释几种神经退行性疾病的生物物理原因。这种见解也给了我们 使用特定的核酸序列和结构来控制和研究蛋白质聚集的机会。我们的 初步数据还表明，含四链体的伴侣序列也有效 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链体 细胞中具有类似伴侣的作用的结构，并研究了伴侣活性的结构基础。 这些研究共同为对蛋白质稳态的新理解及其如何奠定了基础 与核酸生物学有关。这些信息将来将至关重要，以帮助对抗多种蛋白质 错误折叠和聚集疾病。