Protein Structure, Amino Acid Composition And Sequence Determine Proteome Vulnerability To Oxidation-Induced Damage

Oxidative stress alters cell viability, from microorganism irradiation sensitivity to human aging and neurodegeneration. Deleterious effects of protein carbonylation by reactive oxygen species (ROS) make understanding molecular properties determiningROS susceptibility essential. The radiation-resistant bacteriumDeinococcus radioduransaccumulates less carbonylation than sensitive organisms, making it a key model for deciphering properties governing oxidative stress resistance. We integrated shotgun redox proteomics, structural systems biology, and machine learning to resolve properties determining protein damage by gamma-irradiation inEscherichia coliandD. radioduransat multiple scales. Local accessibility, charge, and lysine enrichment accurately predictROSsusceptibility. Lysine, methionine, and cysteine usage also contribute toROSresistance of theD. radioduransproteome. Our model predicts proteome maintenance machinery, and proteins protecting againstROSare more resistant inD. radiodurans. Our findings substantiate that protein-intrinsic protection impacts oxidative stress resistance, identifying causal molecular properties.