Molecular Chaperone-mediated Regulation of Cell Metabolism

分子伴侣介导的细胞代谢调节

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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，细胞严重依赖高度集成的蛋白质网络提供监视并确保蛋白质不会变得容易受到影响聚集，人类神经系统疾病和癌症的驱动因素。这些网络最重要的是分子分子伴侣及其调节因子，协助蛋白质折叠、运输和降解。由于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这些调节因子跨许多细胞过程。最近，我们还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对其生存和增殖至关重要的必需生物分子。然而，我们的关于分子伴侣如何识别和作用于这些酶的知识在很大程度上仍然难以捉摸。拟议的研究结合了超分辨率荧光显微镜、生化和分子生物学工具，以及蛋白质组学分析研究伴侣如何调节常见现象代谢途径，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对细胞如何响应营养供应变化以满足生物质需求的基本了解，提供对导致疾病的失调分子机制的见解，并激发新的治疗方法针对细胞代谢的策略。