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

Patrizia Marinelli, Susanna Navarro, Ricardo Graña-Montes, Manuel Bañó-Polo, María Rosario Fernández, Elena Papaleo, Salvador Ventura

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9 Citations (Scopus)

Abstract

© 2017 The Authors 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.
Original languageEnglish
Pages (from-to)566-575
JournalRedox Biology
Volume14
DOIs
Publication statusPublished - 1 Apr 2018

Keywords

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

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