Highly Charged Proteins are the Achilles' Heel of Aging Proteomes

Abstract

As cells and organisms age, their biomolecules suffer increasing amounts of oxidative damage. Proteins are key targets, with roughly half of the protein molecules in an old organism having some form of damage, averaging about one amino acid alteration per protein. The dominant mechanism by which oxidative damage affects proteins and results in the phenotypes of aging is still unknown. Here we show that the random changes of side-chain charge induced by oxidative damage is a dominant source of protein stability loss in aging cells. Using an established treatment of protein electrostatics, we find that short, highly charged proteins are particularly susceptible to large losses in folding stability from single oxidation that can exceed the entire stability of their native state. This mechanism identifies 20 proteins previously identified as important in aging that fit the profile as being at high risk for electrostatic destabilization from the smallest levels of oxidation. The list includes histones and telomeric proteins, as well as transcription factors, ribosomal proteins, and acetylases and deacetylases. The protein categories we find to be at high risk of destabilization also closely correlate with those known to become increasingly aggregation-prone in aging cells. This mechanism should be useful for better understanding oxidative damage to proteins in aging cells and as a means of identifying susceptible proteins from sequence alone.