Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-11470-9
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Funding
- french National Research Agency [ANR-17-CE11-0021, ANR AA17-PPPPCE11-0000034-02, ANR-11-LABX-0011-01]
- Fondation pour la Recherche Medicale
- MINECO [CTQ2014-52658-R, CTQ2017-84779-R]
- Universite de Strasbourg
- French Proteomic Infrastructure (ProFI) [ANR-10-INBS-08-03]
- GIS IBiSA
- Region Alsace
- Institut de Recherche Servier
- DFG [SCHU 1251/17-1, SPP 1927]
- Agence Nationale de la Recherche (ANR) [ANR-17-CE11-0021] Funding Source: Agence Nationale de la Recherche (ANR)
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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.
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