Highly Charged Proteins: The Achilles' Heel of Aging Proteomes

As cells and organisms age, their proteins sustain increasing amounts of oxidative damage. It is estimated that half of all proteins are damaged in old organisms, yet the dominant mechanisms by which damage affects proteins and cellular phenotypes are not known. Here, we show that random modification of side chain charge induced by oxidative damage is likely to be a dominant source of protein stability loss in aging cells. Using an established model of protein electrostatics, we find that short, highly charged proteins are particularly susceptible to large destabilization from even a single side chain oxidation event. This mechanism identifies 20 proteins previously established to be important in aging that are at particularly high risk for oxidative destabilization, including transcription factors, histone and histone-modifying proteins, ribosomal and telomeric proteins, and proteins essential for homeostasis. Cellular processes enriched in high-risk proteins are shown to be particularly abundant in the aggregates of old organisms.