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  • Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols.

Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols.

Nature communications (2015-01-20)
Aubérie Parent, Xavier Elduque, David Cornu, Laura Belot, Jean-Pierre Le Caer, Anna Grandas, Michel B Toledano, Benoit D'Autréaux
ZUSAMMENFASSUNG

Friedreich's ataxia is a severe neurodegenerative disease caused by the decreased expression of frataxin, a mitochondrial protein that stimulates iron-sulfur (Fe-S) cluster biogenesis. In mammals, the primary steps of Fe-S cluster assembly are performed by the NFS1-ISD11-ISCU complex via the formation of a persulfide intermediate on NFS1. Here we show that frataxin modulates the reactivity of NFS1 persulfide with thiols. We use maleimide-peptide compounds along with mass spectrometry to probe cysteine-persulfide in NFS1 and ISCU. Our data reveal that in the presence of ISCU, frataxin enhances the rate of two similar reactions on NFS1 persulfide: sulfur transfer to ISCU leading to the accumulation of a persulfide on the cysteine C104 of ISCU, and sulfur transfer to small thiols such as DTT, L-cysteine and GSH leading to persulfuration of these thiols and ultimately sulfide release. These data raise important questions on the physiological mechanism of Fe-S cluster assembly and point to a unique function of frataxin as an enhancer of sulfur transfer within the NFS1-ISD11-ISCU complex.

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