Active site CP -loop dynamics modulate substrate binding, catalysis, oligomerization, stability, over-oxidation and recycling of 2-Cys Peroxiredoxins

Free Radical Biology & Medicine
Neelagandan KamariahGerhard Grüber

Abstract

Peroxiredoxins (Prxs) catalyse the rapid reduction of hydrogen peroxide, organic hydroperoxide and peroxynitrite, using a fully conserved peroxidatic cysteine (CP) located in a conserved sequence Pxxx(T/S)xxCP motif known as CP-loop. In addition, Prxs are involved in cellular signaling pathways and regulate several redox-dependent process related disease. The effective catalysis of Prxs is associated with alterations in the CP-loop between reduced, Fully Folded (FF), and oxidized, Locally Unfolded (LU) conformations, which are linked to dramatic changes in the oligomeric structure. Despite many studies, little is known about the precise structural and dynamic roles of the CP-loop on Prxs functions. Herein, the comprehensive biochemical and biophysical studies on Escherichia coli alkyl hydroperoxide reductase subunit C (EcAhpC) and the CP-loop mutants, EcAhpC-F45A and EcAhpC-F45P reveal that the reduced form of the CP-loop adopts conformational dynamics, which is essential for effective peroxide reduction. Furthermore, the point mutants alter the structure and dynamics of the reduced form of the CP-loop and, thereby, affect substrate binding, catalysis, oligomerization, stability and overoxidiation. In the oxidized form, due to ...Continue Reading

Citations

Feb 29, 2020·Journal of Biomolecular Structure & Dynamics·Leonardo Henrique Franca de LimaKlaus Roman Liedl
Apr 11, 2018·Antioxidants & Redox Signaling·David YoungJoris Messens

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