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Title: Physiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide- processing functions of ferredoxin-2 and frataxin
Author: 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
Keywords: Malalties neurodegeneratives
Neurodegenerative Diseases
Issue Date: 2019
Publisher: Nature Publishing Group
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.
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It is part of: Nature Communications, 2019, vol. 10, p. 3566
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ISSN: 2041-1723
Appears in Collections:Articles publicats en revistes (Química Inorgànica i Orgànica)

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