Title
Physiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide-processing functions of ferredoxin-2 and frataxin
Author
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, Benoit D’Autréaux
Year
2019
Journal
Nature Communications
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.
Full Article
Instrument
J-815
Keywords
Circular dichroism, Ligand binding, Protein structure, Biochemistry, Inorganic chemistry