How Do Chaperones Protect a Cell's Proteins from Oxidative Damage?

The accumulation of protein damage in aging organisms is thought to contribute to many aging-related diseases. Yet the properties determining which proteins are most susceptible remain poorly understood. Are certain conformations more vulnerable? Which chaperones are the main guardians? We address these questions with a system-wide model of E. coli proteostasis. By predicting how proteins with different folding properties respond to each chaperone's concentration, the model computes “damage fingerprints” that identify unfolded conformations as the major damage target. What matters most is not a protein's stability or difficulty of folding, but its dwell time in an unfolded state. The main guardian chaperone is DnaK because its client proteins spend more time unfolded than clients of GroEL, providing a mechanism for why the cell's capacity to handle stress is more sensitive to DnaK levels. Also, we find that chaperones are protectors, not recyclers. This model describes how cells resist stress and indicates that designing chaperone-targeting drugs may require whole-cell, system-wide modeling. We present a computational model of cell-wide proteostasis in E. coli to understand the role of chaperones in regulating oxidative damage. By investigating how a cell's whole proteostasis network traffics different subsets of its proteome, the model highlights the cell's algorithms for handling stress. This study provides broader insight into the role of chaperones in maintaining cellular health in aging and aging-related diseases.