title: Mammalian frataxin controls sulfur production and iron entry during de novo Fe4S4 cluster assembly.
abstract: Iron-sulfur (Fe-S) cluster-containing proteins are essential components of cells. In eukaryotes, Fe-S clusters are synthesized by the mitochondrial iron-sulfur cluster (ISC) machinery and the cytosolic iron-sulfur assembly (CIA) system. In the mammalian ISC machinery, preassembly of the Fe-S cluster on the scaffold protein (ISCU) involves a cysteine desulfurase complex (NFS1/ISD11) and frataxin (FXN), the protein deficient in Friedreich's ataxia. Here, by comparing the biochemical and spectroscopic properties of quaternary (ISCU/NFS1/ISD11/FXN) and ternary (ISCU/NFS1/ISD11) complexes, we show that FXN stabilizes the quaternary complex and controls iron entry to the complex through activation of cysteine desulfurization. Furthermore, we show for the first time that in the presence of iron and L-cysteine, an [Fe(4)S(4)] cluster is formed within the quaternary complex that can be transferred to mammalian aconitase (mACO2) to generate an active enzyme. In the absence of FXN, although the ternary complex can assemble an Fe-S cluster, the cluster is inefficiently transferred to ACO2. Taken together, these data help to unravel further the Fe-S cluster assembly process and the molecular basis of Friedreich's ataxia.
authors.affiliation: Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Colin
authors.forename: Alain
authors.initials: A
authors.lastname: Martelli
authors.forename: Martin
authors.initials: M
authors.lastname: Clémancey
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Latour
authors.forename: Serge
authors.initials: S
authors.lastname: Gambarelli
authors.forename: Laura
authors.initials: L
authors.lastname: Zeppieri
authors.forename: Catherine
authors.initials: C
authors.lastname: Birck
authors.forename: Adeline
authors.initials: A
authors.lastname: Page
authors.forename: Hélène
authors.initials: H
authors.lastname: Puccio
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ollagnier de Choudens
mesh_terms: D000818:Animals; D056831:Coordination Complexes / Q000737:chemistry; D006801:Humans; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000502:physiology*; D007506:Iron-Sulfur Proteins / Q000737:chemistry*; D008958:Models, Molecular; D013455:Sulfur / Q000378:metabolism*; D000096923:Frataxin
chemical_list: D056831:Coordination Complexes; D007501:Iron; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D013455:Sulfur; D000096923:Frataxin