Gervason, SylvainLarkem, DjabirMansour, Amir BenBotzanowski, ThomasMüller, Christina S.Pecqueur, LudovicLe Pavec, GwenaelleDelaunay-Moisan, AgnèsBrun Cubero, OmarAgramunt, JordiGrandas Sagarra, AnnaFontecave, MarcSchünemann, VolkerCianférani, SarahSizun, ChristinaToledano, Michel B.D'Autréaux, Benoit2019-09-192019-09-1920192041-1723https://hdl.handle.net/2445/140541Iron-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.13 p.application/pdfengcc-by (c) Gervason, Sylvain et al., 2019http://creativecommons.org/licenses/by/3.0/esMalalties neurodegenerativesBioquímicaBiosíntesiProteïnesNeurodegenerative DiseasesBiochemistryBiosynthesisProteinsinfo:eu-repo/semantics/article6912562019-09-19info:eu-repo/semantics/openAccess31395877