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Physiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide-processing functions of ferredoxin-2 and frataxin

Author

Listed:
  • Sylvain Gervason

    (Université Paris‐Saclay)

  • Djabir Larkem

    (Université Paris‐Saclay)

  • Amir Ben Mansour

    (Université Paris‐Saclay)

  • Thomas Botzanowski

    (Université de Strasbourg, CNRS, IPHC UMR 7178)

  • Christina S. Müller

    (Technische Universität Kaiserslautern)

  • Ludovic Pecqueur

    (CNRS UMR 8229, PSL Research University)

  • Gwenaelle Le Pavec

    (Université Paris‐Saclay)

  • Agnès Delaunay-Moisan

    (Université Paris‐Saclay)

  • Omar Brun

    (Universitat de Barcelona)

  • Jordi Agramunt

    (Universitat de Barcelona)

  • Anna Grandas

    (Universitat de Barcelona)

  • Marc Fontecave

    (CNRS UMR 8229, PSL Research University)

  • Volker Schünemann

    (Technische Universität Kaiserslautern)

  • Sarah Cianférani

    (Université de Strasbourg, CNRS, IPHC UMR 7178)

  • Christina Sizun

    (CNRS, Université Paris Saclay)

  • Michel B. Tolédano

    (Université Paris‐Saclay)

  • Benoit D’Autréaux

    (Université Paris‐Saclay)

Abstract

Iron-sulfur (Fe-S) clusters are essential protein cofactors whose biosynthetic defects lead to severe diseases among which is Friedreich’s ataxia caused by impaired expression of frataxin (FXN). Fe-S clusters are biosynthesized on the scaffold protein ISCU, with cysteine desulfurase NFS1 providing sulfur as persulfide and ferredoxin FDX2 supplying electrons, in a process stimulated by FXN but not clearly understood. Here, we report the breakdown of this process, made possible by removing a zinc ion in ISCU that hinders iron insertion and promotes non-physiological Fe-S cluster synthesis from free sulfide in vitro. By binding zinc-free ISCU, iron drives persulfide uptake from NFS1 and allows persulfide reduction into sulfide by FDX2, thereby coordinating sulfide production with its availability to generate Fe-S clusters. FXN stimulates the whole process by accelerating persulfide transfer. We propose that this reconstitution recapitulates physiological conditions which provides a model for Fe-S cluster biosynthesis, clarifies the roles of FDX2 and FXN and may help develop Friedreich’s ataxia therapies.

Suggested Citation

  • Sylvain Gervason & Djabir Larkem & Amir Ben Mansour & Thomas Botzanowski & Christina S. Müller & Ludovic Pecqueur & Gwenaelle Le Pavec & Agnès Delaunay-Moisan & Omar Brun & Jordi Agramunt & Anna Grand, 2019. "Physiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide-processing functions of ferredoxin-2 and frataxin," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11470-9
    DOI: 10.1038/s41467-019-11470-9
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    Cited by:

    1. Vinzent Schulz & Ralf Steinhilper & Jonathan Oltmanns & Sven-A. Freibert & Nils Krapoth & Uwe Linne & Sonja Welsch & Maren H. Hoock & Volker Schünemann & Bonnie J. Murphy & Roland Lill, 2024. "Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Sven-A. Freibert & Michal T. Boniecki & Claudia Stümpfig & Vinzent Schulz & Nils Krapoth & Dennis R. Winge & Ulrich Mühlenhoff & Oliver Stehling & Miroslaw Cygler & Roland Lill, 2021. "N-terminal tyrosine of ISCU2 triggers [2Fe-2S] cluster synthesis by ISCU2 dimerization," Nature Communications, Nature, vol. 12(1), pages 1-15, December.

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