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Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols

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  • Aubérie Parent

    (Institut de Chimie des Substances Naturelles, UPR2301, Centre de Recherche de Gif, Centre National de la Recherche Scientifique)

  • Xavier Elduque

    (Departament de Química Orgànica i IBUB, Facultat de Química, Universitat de Barcelona)

  • David Cornu

    (Plateforme IMAGIF, Centre de Recherche de Gif, Centre National de la Recherche Scientifique)

  • Laura Belot

    (Institut de Chimie des Substances Naturelles, UPR2301, Centre de Recherche de Gif, Centre National de la Recherche Scientifique)

  • Jean-Pierre Le Caer

    (Institut de Chimie des Substances Naturelles, UPR2301, Centre de Recherche de Gif, Centre National de la Recherche Scientifique)

  • Anna Grandas

    (Departament de Química Orgànica i IBUB, Facultat de Química, Universitat de Barcelona)

  • Michel B. Toledano

    (Laboratoire Stress Oxydant et Cancer, Service de Biologie Intégrative et de Génétique Moléculaire, Institut de Biologie et de Technologie de Saclay, Commissariat à l’Energie Atomique et aux Energies Alternatives)

  • Benoit D’Autréaux

    (Institut de Chimie des Substances Naturelles, UPR2301, Centre de Recherche de Gif, Centre National de la Recherche Scientifique)

Abstract

Friedreich’s ataxia is a severe neurodegenerative disease caused by the decreased expression of frataxin, a mitochondrial protein that stimulates iron–sulfur (Fe-S) cluster biogenesis. In mammals, the primary steps of Fe-S cluster assembly are performed by the NFS1–ISD11–ISCU complex via the formation of a persulfide intermediate on NFS1. Here we show that frataxin modulates the reactivity of NFS1 persulfide with thiols. We use maleimide-peptide compounds along with mass spectrometry to probe cysteine-persulfide in NFS1 and ISCU. Our data reveal that in the presence of ISCU, frataxin enhances the rate of two similar reactions on NFS1 persulfide: sulfur transfer to ISCU leading to the accumulation of a persulfide on the cysteine C104 of ISCU, and sulfur transfer to small thiols such as DTT, L-cysteine and GSH leading to persulfuration of these thiols and ultimately sulfide release. These data raise important questions on the physiological mechanism of Fe-S cluster assembly and point to a unique function of frataxin as an enhancer of sulfur transfer within the NFS1–ISD11–ISCU complex.

Suggested Citation

  • Aubérie Parent & Xavier Elduque & David Cornu & Laura Belot & Jean-Pierre Le Caer & Anna Grandas & Michel B. Toledano & Benoit D’Autréaux, 2015. "Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms6686
    DOI: 10.1038/ncomms6686
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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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