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.

项目摘要/摘要 蛋白质组的完整性不断受到挑战。为了维持蛋白质稳态，细胞严重依赖 在高度集成的蛋白质网络上提供监视并确保蛋白质不容易受到影响 聚集，人类神经疾病和癌症的驱动力。这些网络的最重要的是分子 伴侣及其调节剂，有助于蛋白质折叠，运输和降解。作为多样性 需要这些伴侣的蛋白质增加，我们对重要性有了更广泛的了解 在许多细胞过程中的这些调节剂中。最近，我们发现了分子伴侣 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 有效地产生必要的生物分子对于它们的生存和增殖至关重要。但是，我们的 了解伴侣如何识别和对这些酶作用的知识在很大程度上仍然难以捉摸。提议 研究结合了超分辨率的荧光显微镜，生化和分子生物学工具以及 蛋白质组学分析以调查伴侣如何调节通常观察到的现象 代谢途径，包括相分离的代谢酶组件的形成以促进 底物引导，大型多域酶的折叠以驱动紧密耦合活动，并折叠 伴侣介导的自噬诱导代谢酶降解。这些发现将加深我们 对细胞对营养可用性变化的反应以满足生物质需求的基本了解， 提供有关驱动疾病的失调的分子机制的见解，并激发新的治疗性 针对细胞代谢的策略。