title: Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols.
abstract: 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.
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR2301, Centre de Recherche de Gif, Centre National de la Recherche Scientifique, 1 avenue de la terrasse, 91191 Gif Sur Yvette, France.
authors.forename: Aubérie
authors.initials: A
authors.lastname: Parent
authors.affiliation: Departament de Química Orgànica i IBUB, Facultat de Química, Universitat de Barcelona, Marti i Franques 1-11, E-08028 Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Elduque
authors.affiliation: Plateforme IMAGIF, Centre de Recherche de Gif, Centre National de la Recherche Scientifique, 1 avenue de le terrasse, 91191 Gif Sur Yvette, France.
authors.forename: David
authors.initials: D
authors.lastname: Cornu
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR2301, Centre de Recherche de Gif, Centre National de la Recherche Scientifique, 1 avenue de la terrasse, 91191 Gif Sur Yvette, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Belot
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR2301, Centre de Recherche de Gif, Centre National de la Recherche Scientifique, 1 avenue de la terrasse, 91191 Gif Sur Yvette, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Le Caer
authors.affiliation: Departament de Química Orgànica i IBUB, Facultat de Química, Universitat de Barcelona, Marti i Franques 1-11, E-08028 Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Grandas
authors.affiliation: Laboratoire Stress Oxydant et Cancer, Service de Biologie Intégrative et de Génétique Moléculaire, Institut de Biologie et de Technologie de Saclay, Commissariat à l'Energie Atomique et aux Energies Alternatives, F-91191 Gif Sur Yvette, France.
authors.forename: Michel B
authors.initials: MB
authors.lastname: Toledano
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR2301, Centre de Recherche de Gif, Centre National de la Recherche Scientifique, 1 avenue de la terrasse, 91191 Gif Sur Yvette, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: D'Autréaux
mesh_terms: D013437:Carbon-Sulfur Lyases / Q000737:chemistry / Q000378:metabolism*; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D033862:Iron-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D013058:Mass Spectrometry; D012984:Software; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism*; D013440:Sulfides / Q000737:chemistry / Q000378:metabolism; D000096923:Frataxin
chemical_list: D013437:Carbon-Sulfur Lyases; D003545:Cysteine; D005978:Glutathione; D033862:Iron-Binding Proteins; D013438:Sulfhydryl Compounds; D013440:Sulfides; D000096923:Frataxin; C051552:persulfides; C513492:NFS1 protein, human