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Mechanism of oxidative inactivation of human presequence protease by hydrogen peroxide
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2014 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 77, 57-63 p.Article in journal (Refereed) Published
Abstract [en]

The mitochondrial presequence protease (PreP) is a member of the pitrilysin class of metalloproteases. It degrades the mitochondrial targeting presequences of mitochondria-localized proteins as well as unstructured peptides such as amyloid-beta peptide. The specific activity of PreP is reduced in Alzheimer patients and animal models of Alzheimer disease. The loss of activity can be mimicked in vitro by exposure to oxidizing conditions, and indirect evidence suggested that inactivation was due to methionine oxidation. We performed peptide mapping analyses to elucidate the mechanism of inactivation. None of the 24 methionine residues in recombinant human PreP was oxidized. We present evidence that inactivation is due to oxidation of cysteine residues and consequent oligomerization through intermolecular disulfide bonds. The most susceptible cysteine residues to oxidation are Cys34, Cys112, and Cys119. Most, but not all, of the activity loss is restored by the reducing agent dithiothreitol. These findings elucidate a redox mechanism for regulation of PreP and also provide a rational basis for therapeutic intervention in conditions characterized by excessive oxidation of PreP.

Place, publisher, year, edition, pages
2014. Vol. 77, 57-63 p.
Keyword [en]
Presequence protease, Protein oxidation, Peptide degradation, Cysteine oxidation, Methionine sulfoxide, Free radicals
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:su:diva-112905DOI: 10.1016/j.freeradbiomed.2014.08.016ISI: 000346392500007OAI: diva2:782735


Available from: 2015-01-22 Created: 2015-01-19 Last updated: 2015-01-22Bibliographically approved

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Teixeira, Pedro FilipeGlaser, Elzbieta
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