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

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 Grandas, Marc Fontecave, Volker Schünemann, Sarah Cianférani, Christina Sizun, Michel B. Tolédano and Benoit D’Autréaux ()
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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

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11470-9

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