Grant: Project Grant

Proteins are the workhorses of our cells and must fold into precise three-dimensional shapes to function properly. Cells are equipped with quality-control systems that help proteins fold and eliminate those that are damaged. However, when a protein carries a permanent mutation, these systems can sometimes be too aggressive, destroying proteins that retain partial function. This can result in harmful loss of activity. This issue is highly relevant, as more than 275,000 disease-causing protein mutations have been identified in humans. Our research focuses on mutated proteins located in the cytosol, the main compartment of the cell. We aim to understand how cells decide whether to refold these altered proteins or target them for destruction. We have identified "helper" proteins, called chaperones, that bind more strongly to mutated proteins. We also discovered short protein segments known as degrons, which act as built-in "disposal tags" when exposed. Importantly, some chaperones that assist folding can also help direct proteins toward degradation. In this project, we will: (1) determine how a chaperone and a partner enzyme we identified recognize exposed degrons and promote protein destruction; (2) define which degrons become exposed when a protein is destabilized by mutation; and (3) systematically identify degrons across human proteins, determine which are enriched in disease-associated mutations, and uncover the cellular machinery that recognizes them. By understanding how cells make "fold or destroy" decisions, we aim to explain how specific mutations lead to disease. This knowledge may ultimately guide strategies to fine-tune protein quality control and rescue partially functional proteins instead of eliminating them prematurely.