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Mycoredoxin-1 is one of the missing links in the oxidative stress defence mechanism of Mycobacteria

Authors

  • Koen Van Laer,

    1. Department of Structural Biology, Vlaams Instituut voor Biotechnologie, Brussels, Belgium
    2. Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium
    3. Brussels Center for Redox Biology, Brussels, Belgium
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  • Lieven Buts,

    1. Department of Structural Biology, Vlaams Instituut voor Biotechnologie, Brussels, Belgium
    2. Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium
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  • Nicolas Foloppe,

    1. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
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  • Didier Vertommen,

    1. de Duve Institute, Université catholique de Louvain, Brussels, Belgium
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  • Karolien Van Belle,

    1. Department of Structural Biology, Vlaams Instituut voor Biotechnologie, Brussels, Belgium
    2. Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium
    3. Brussels Center for Redox Biology, Brussels, Belgium
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  • Khadija Wahni,

    1. Department of Structural Biology, Vlaams Instituut voor Biotechnologie, Brussels, Belgium
    2. Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium
    3. Brussels Center for Redox Biology, Brussels, Belgium
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  • Goedele Roos,

    1. Department of Structural Biology, Vlaams Instituut voor Biotechnologie, Brussels, Belgium
    2. Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium
    3. Brussels Center for Redox Biology, Brussels, Belgium
    4. Algemene Chemie, Vrije Universiteit Brussel, Brussels, Belgium
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  • Lennart Nilsson,

    1. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
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  • Luis M. Mateos,

    1. Department of Molecular Biology, Area of Microbiology, University of León, León, Spain
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  • Mamta Rawat,

    1. Department of Biology, California State University, Fresno, CA, USA
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  • Nico A. J. van Nuland,

    Corresponding author
    1. Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium
    • Department of Structural Biology, Vlaams Instituut voor Biotechnologie, Brussels, Belgium
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  • Joris Messens

    Corresponding author
    1. Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium
    2. Brussels Center for Redox Biology, Brussels, Belgium
    • Department of Structural Biology, Vlaams Instituut voor Biotechnologie, Brussels, Belgium
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For correspondence. E-mail joris.messens@vib-vub.be; nico.vannuland@vib-vub.be; Tel. (+32) 2 6291992; Fax (+32) 2 6291963.

Summary

To survive hostile conditions, the bacterial pathogen Mycobacterium tuberculosis produces millimolar concentrations of mycothiol as a redox buffer against oxidative stress. The reductases that couple the reducing power of mycothiol to redox active proteins in the cell are not known. We report a novel mycothiol-dependent reductase (mycoredoxin-1) with a CGYC catalytic motif. With mycoredoxin-1 and mycothiol deletion strains of Mycobacterium smegmatis, we show that mycoredoxin-1 and mycothiol are involved in the protection against oxidative stress. Mycoredoxin-1 acts as an oxidoreductase exclusively linked to the mycothiol electron transfer pathway and it can reduce S-mycothiolated mixed disulphides. Moreover, we solved the solution structures of oxidized and reduced mycoredoxin-1, revealing a thioredoxin fold with a putative mycothiol-binding site. With HSQC snapshots during electron transport, we visualize the reduction of oxidized mycoredoxin-1 as a function of time and find that mycoredoxin-1 gets S-mycothiolated on its N-terminal nucleophilic cysteine. Mycoredoxin-1 has a redox potential of −218 mV and hydrogen bonding with neighbouring residues lowers the pKa of its N-terminal nucleophilic cysteine. Determination of the oxidized and reduced structures of mycoredoxin-1, better understanding of mycothiol-dependent reactions in general, will likely give new insights in how M. tuberculosis survives oxidative stress in human macrophages.

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