Protein structure, amino acid composition and sequence determine proteome vulnerability to oxidation-induced damage

Area of Science:

• Biochemistry
• Molecular Biology
• Microbiology

Background:

• Oxidative stress, caused by reactive oxygen species (ROS), significantly impacts cell viability across organisms, contributing to aging and neurodegeneration.
• Protein carbonylation is a key damaging effect of ROS, making the identification of molecular factors influencing protein susceptibility crucial.
• The radiation-resistant bacterium Deinococcus radiodurans serves as a valuable model due to its lower accumulation of protein carbonylation compared to sensitive species.

Purpose of the Study:

• To elucidate the molecular properties that determine protein susceptibility and resistance to oxidative stress, specifically from gamma irradiation.
• To compare these properties between the robust Deinococcus radiodurans and the more sensitive Escherichia coli.

Main Methods:

• Integration of shotgun redox proteomics to identify protein modifications.
• Application of structural systems biology to analyze protein structures.
• Utilization of machine learning algorithms to predict ROS susceptibility based on molecular features.
• Comparative analysis across multiple scales in both E. coli and D. radiodurans.

Main Results:

• Local accessibility, net charge, and lysine enrichment were identified as accurate predictors of ROS susceptibility.
• Specific amino acid usage, including lysine, methionine, and cysteine, contributes to the ROS resistance of the D. radiodurans proteome.
• Proteome maintenance machinery and ROS-protective proteins exhibit enhanced resistance in D. radiodurans.

Conclusions:

• Protein-intrinsic properties play a significant role in determining oxidative stress resistance.
• The study identifies causal molecular properties that underlie differential susceptibility to ROS damage.
• Findings provide a foundation for understanding and potentially enhancing cellular defense mechanisms against oxidative damage.