Every cell constantly makes and destroys proteins. When a newly synthesized protein folds incorrectly, it needs to be identified and eliminated quickly to prevent cellular damage. This study used advanced structural proteomics and isotopic labeling to map exactly how the cell's cleanup machinery recognizes these defective proteins. The key discovery: misfolded proteins accidentally expose lysine amino acids that are normally buried deep inside properly folded proteins. These exposed lysines serve as attachment points for ubiquitin, a molecular tag that marks proteins for destruction by the proteasome — the cell's main protein-recycling machine. This work clarifies a fundamental quality-control mechanism and has broad implications for understanding aging, neurodegeneration, and diseases driven by protein misfolding.
