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... More
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.
