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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

How pH Modulates the Dimer-Decamer Interconversion of 2-Cys Peroxiredoxins from the Prx1 Subfamily

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Author(s):
Morais, Mariana A. B. [1] ; Giuseppe, Priscila O. [1] ; Souza, Tatiana A. C. B. [2] ; Alegria, Thiago G. P. [3] ; Oliveira, Marcos A. [4] ; Netto, Luis E. S. [3] ; Murakami, Mario T. [1]
Total Authors: 7
Affiliation:
[1] Ctr Nacl Pesquisa Energia & Mat, Lab Nacl Biociencias, BR-13083970 Campinas, SP - Brazil
[2] Inst Carlos Chagas, Lab Proteom & Engn Proteinas, BR-81350010 Curitiba, Parana - Brazil
[3] Univ Sao Paulo, Dept Genet & Biol Evolutiva, Inst Biociencias, BR-05508900 Sao Paulo, SP - Brazil
[4] Univ Estadual Paulista, Dept Biol, BR-11330900 Sao Vicente, SP - Brazil
Total Affiliations: 4
Document type: Journal article
Source: Journal of Biological Chemistry; v. 290, n. 13, p. 8582-8590, MAR 27 2015.
Web of Science Citations: 21
Abstract

2-Cys peroxiredoxins belonging to the Prx1 subfamily are Cys-based peroxidases that control the intracellular levels of H2O2 and seem to assume a chaperone function under oxidative stress conditions. The regulation of their peroxidase activity as well as the observed functional switch from peroxidase to chaperone involves changes in their quaternary structure. Multiple factors can modulate the oligomeric transitions of 2-Cys peroxiredoxins such as redox state, post-translational modifications, and pH. However, the molecular basis for the pH influence on the oligomeric state of these enzymes is still elusive. Herein, we solved the crystal structure of a typical 2-Cys peroxiredoxin from Leishmania in the dimeric (pH 8.5) and decameric (pH 4.4) forms, showing that conformational changes in the catalytic loop are associated with the pH-induced decamerization. Mutagenesis and biophysical studies revealed that a highly conserved histidine (His(113)) functions as a pH sensor that, at acidic conditions, becomes protonated and forms an electrostatic pair with Asp(76) from the catalytic loop, triggering the decamerization. In these 2-Cys peroxiredoxins, decamer formation is important for the catalytic efficiency and has been associated with an enhanced sensitivity to oxidative inactivation by overoxidation of the peroxidatic cysteine. In eukaryotic cells, exposure to high levels of H2O2 can trigger intracellular pH variations, suggesting that pH changes might act cooperatively with H2O2 and other oligomerization-modulator factors to regulate the structure and function of typical 2-Cys peroxiredoxins in response to oxidative stress. (AU)

FAPESP's process: 10/51730-0 - Functional and structural studies of protein kinases involved in cancer and neglected diseases: towards the development of new inhibitors
Grantee:Jörg Kobarg
Support type: Regular Research Grants
FAPESP's process: 12/24134-3 - Functional and structural studies of peroxiredoxin I from Leishmania braziliensis and Homo sapiens aiming to understand the oligomerization and catalysis mechanisms
Grantee:Mariana Abrahão Bueno de Morais
Support type: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 11/10248-4 - Cloning, expression, purification and structural characterization of the protein tryparedoxin peroxidase from Leishmania braziliensis
Grantee:Mariana Abrahão Bueno de Morais
Support type: Scholarships in Brazil - Scientific Initiation