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urn:hdl:2445/140541 Physiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide- processing functions of ferredoxin-2 and frataxin Gervason, Sylvain Larkem, Djabir Mansour, Amir Ben Botzanowski, Thomas Müller, Christina S. Pecqueur, Ludovic Le Pavec, Gwenaelle Delaunay-Moisan, Agnès Brun Cubero, Omar Agramunt, Jordi Grandas Sagarra, Anna Fontecave, Marc Schünemann, Volker Cianférani, Sarah Sizun, Christina Toledano, Michel B. D'Autréaux, Benoit Malalties neurodegeneratives Bioquímica Biosíntesi Proteïnes Neurodegenerative Diseases Biochemistry Biosynthesis Proteins 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. 2019-09-19T14:47:35Z 2019-09-19T14:47:35Z 2019 2019-09-19T14:47:36Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Reproducció del document publicat a: https://doi.org/10.1038/s41467-019-11470-9 Nature Communications, 2019, vol. 10, p. 3566 https://doi.org/10.1038/s41467-019-11470-9 cc-by (c) Gervason, Sylvain et al., 2019 http://creativecommons.org/licenses/by/3.0/es info:eu-repo/semantics/openAccess Nature Publishing Group Articles publicats en revistes (Química Inorgànica i Orgànica)