A single cysteine post-translational oxidation suffices to compromise globular proteins kinetic stability and promote amyloid formation

作者：Marinelli Patrizia; Navarro Susanna; Grana Montes Ricardo; Bano Polo Manuel; Rosario Fernandez Maria; Papaleo Elena; Ventura Salvador^*

来源：Redox Biology, 2018, 14: 566-575.

DOI：10.1016/j.redox.2017.10.022

• Protein oxidation
• Protein misfolding
• Protein aggregation
• Oxidative stress
• Post-translational modification

Oxidatively modified forms of proteins accumulate during aging. Oxidized protein conformers might act as intermediates in the formation of amyloids in age-related disorders. However, it is not known whether this amyloidogenic conversion requires an extensive protein oxidative damage or it can be promoted just by a discrete, localized post-translational modification of certain residues. Here, we demonstrate that the irreversible oxidation of a single free Cys suffices to severely perturb the folding energy landscape of a stable globular protein, compromise its kinetic stability, and lead to the formation of amyloids under physiological conditions. Experiments and simulations converge to indicate that this specific oxidation-promoted protein aggregation requires only local unfolding. Indeed, a large scale analysis indicates that many cellular proteins are at risk of undergoing this kind of deleterious transition; explaining how oxidative stress can impact cell proteostasis and subsequently lead to the onset of pathological states.

• 出版日期2018-4