Molecular Chaperone-mediated Regulation of Cell Metabolism

分子伴侣介导的细胞代谢调节

• 批准号: 10711735
• 负责人: Anthony M Pedley
• 金额: $ 40.1万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711735
• 关键词: Anabolism; Autophagocytosis; Biochemical; Biomass; Cell physiology; Cells; Cellular Metabolic Process; Complex; Coupled; DNA Repair; Disease; Disease Progression; Ensure; Enzymes; Event; Fluorescence Microscopy; Glycolysis; Human; Knowledge; Mediating; Metabolic; Metabolic Pathway; Molecular; Molecular Biology; Molecular Chaperones; Multiprotein Complexes; Nutrient availability; Phase; Predisposition; Proliferating; Proteins; Proteome; Proteomics; Purines; Regulation; Signal Transduction; human disease; insight; malignant neurologic neoplasms; nervous system disorder; novel therapeutic intervention; protein folding; proteostasis; recruit; tool; ultra high resolution

PROJECT SUMMARY/ABSTRACT The integrity of the proteome is constantly being challenged. To maintain protein homeostasis, cells rely heavily on highly integrated protein networks to provide surveillance and ensure proteins do not become susceptible to aggregation, a driver of human neurological diseases and cancers. Paramount to these networks are molecular chaperones and their regulators, which assist in protein folding, transport, and degradation. As the diversity of proteins that require these chaperones increases, we have gained a broader understanding of the importance of these regulators across many cellular processes. Recently, we discovered molecular chaperones also influence cell metabolism by acting on key metabolic enzymes within glycolysis and purine biosynthesis to efficiently produce the necessary biomolecules critical for their survival and proliferation. However, our knowledge of how chaperones recognize and act on these enzymes remains largely elusive. The proposed studies combine super-resolution fluorescence microscopy, biochemical and molecular biology tools, and proteomic analyses to investigate the how chaperones regulate commonly observed phenomena across metabolic pathways including the formation of phase separated metabolic enzyme assemblies to facilitate substrate channeling, the folding of large multi-domain enzymes to drive tightly coupled activities, and the induced degradation of metabolic enzymes by chaperone-mediated autophagy. These findings will deepen our fundamental understanding of how cells respond to changes in nutrient availability to meet biomass demand, provide insights into the molecular mechanisms of dysregulation that drive disease, and inspire new therapeutic strategies targeting cell metabolism.

项目总结/摘要 蛋白质组的完整性不断受到挑战。为了维持蛋白质的稳态，细胞严重依赖 高度整合的蛋白质网络，以提供监测，并确保蛋白质不会变得容易受到 聚集是人类神经系统疾病和癌症的驱动因素。对这些网络至关重要的是分子 分子伴侣及其调节剂，其协助蛋白质折叠、运输和降解。的多样性 需要这些分子伴侣的蛋白质增加，我们对蛋白质的重要性有了更广泛的理解。 在许多细胞过程中发挥作用。最近，我们发现分子伴侣也 通过作用于糖酵解和嘌呤生物合成中的关键代谢酶来影响细胞代谢， 有效地产生对它们的生存和增殖至关重要的必要生物分子。但我们的 伴侣如何识别和作用于这些酶的知识仍然很难理解。拟议 研究结合了联合收割机超分辨率荧光显微镜、生物化学和分子生物学工具， 蛋白质组学分析，以研究伴侣如何调节常见的现象， 代谢途径，包括形成相分离的代谢酶组件，以促进 底物通道，大型多结构域酶的折叠以驱动紧密耦合的活性，以及 通过分子伴侣介导的自噬诱导代谢酶的降解。这些发现将加深我们的 基本了解细胞如何响应营养物质可用性的变化，以满足生物量的需求， 提供对驱动疾病的失调的分子机制的见解，并激发新的治疗方法， 针对细胞代谢的策略。