Oxidation, inactivation and aggregation of protein disulfide isomerase promoted by the bicarbonate-dependent peroxidase activity of human superoxide dismutase

[Display omitted] •PDI was challenged with the bicarbonate-dependent peroxidase activity of hSOD1.•The challenge resulted in PDI oxidation, inactivation and covalent aggregation.•MS analysis of PDI radical adducts evidenced radicals on 3 tyrosine residues.•PDI was also oxidized, inactivated and aggregated by CO3− and by UV light.•PDI susceptibility to aggregation may contribute to degenerative processes. Protein disulfide isomerase (PDI) is a dithiol–disulfide oxidoreductase that has essential roles in redox protein folding. PDI has been associated with protective roles against protein aggregation, a hallmark of neurodegenerative diseases. Intriguingly, PDI has been detected in the protein inclusions found in the central nervous system of patients of neurodegenerative diseases. Oxidized proteins are also consistently detected in such patients, but the agents that promote these oxidations remain undefined. A potential trigger of protein oxidation is the bicarbonate-dependent peroxidase activity of the human enzyme superoxide dismutase 1 (hSOD1). Therefore, we examined the effects of this activity on PDI structure and activity. The results showed that PDI was oxidized to radicals that lead to PDI inactivation and aggregation. The aggregates are huge and apparently produced by covalent cross-links. Spin trapping experiments coupled with MS analysis indicated that at least 3 residues of PDI are oxidized to tyrosyl radicals (Y63, Y116 and Y327). Parallel experiments showed that PDI is also oxidized to radicals, inactivated and aggregated by the action of photolytically generated carbonate radical and by UV light. PDI is prone to inactivation and aggregation by one-electron oxidants and UV light probably because of its high content of aromatic amino acids.