title: Structural bases for the interaction of frataxin with the central components of iron-sulphur cluster assembly.
abstract: Reduced levels of frataxin, an essential protein of as yet unknown function, are responsible for causing the neurodegenerative pathology Friedreich's ataxia. Independent reports have linked frataxin to iron-sulphur cluster assembly through interactions with the two central components of this machinery: desulphurase Nfs1/IscS and the scaffold protein Isu/IscU. In this study, we use a combination of biophysical methods to define the structural bases of the interaction of CyaY (the bacterial orthologue of frataxin) with the IscS/IscU complex. We show that CyaY binds IscS as a monomer in a pocket between the active site and the IscS dimer interface. Recognition does not require iron and occurs through electrostatic interactions of complementary charged residues. Mutations at the complex interface affect the rates of enzymatic cluster formation. CyaY binding strengthens the affinity of the IscS/IscU complex. Our data suggest a new paradigm for understanding the role of frataxin as a regulator of IscS functions.
authors.affiliation: National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
authors.forename: Filippo
authors.initials: F
authors.lastname: Prischi
authors.forename: Petr V
authors.initials: PV
authors.lastname: Konarev
authors.forename: Clara
authors.initials: C
authors.lastname: Iannuzzi
authors.forename: Chiara
authors.initials: C
authors.lastname: Pastore
authors.forename: Salvatore
authors.initials: S
authors.lastname: Adinolfi
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Martin
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
mesh_terms: D020134:Catalytic Domain; D033862:Iron-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000737:chemistry* / Q000378:metabolism*; D008962:Models, Theoretical; D009154:Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D000096923:Frataxin
chemical_list: D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D000096923:Frataxin