Thursday, January 2, 2025
1/2/2025
PROJECT SUMMARY / ABSTRACT There is no change to the proposed work outlined in the parent R35 proposal (R35GM150481). 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.
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