title: The structures of frataxin oligomers reveal the mechanism for the delivery and detoxification of iron.
abstract: Defects in the mitochondrial protein frataxin are responsible for Friedreich ataxia, a neurodegenerative and cardiac disease that affects 1:40,000 children. Here, we present the crystal structures of the iron-free and iron-loaded frataxin trimers, and a single-particle electron microscopy reconstruction of a 24 subunit oligomer. The structures reveal fundamental aspects of the frataxin mechanism. The trimer has a central channel in which one atom of iron binds. Two conformations of the channel with different metal-binding affinities suggest that a gating mechanism controls whether the bound iron is delivered to other proteins or transferred to detoxification sites. The trimer constitutes the basic structural unit of the 24 subunit oligomer. The architecture of this oligomer and several features of the trimer structure demonstrate striking similarities to the iron-storage protein ferritin. The data reveal how stepwise assembly provides frataxin with the structural flexibility to perform two functions: metal delivery and detoxification.
authors.affiliation: Department of Molecular Biophysics, Center for Chemistry and Chemical Engineering, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Karlberg
authors.forename: Ulrika
authors.initials: U
authors.lastname: Schagerlöf
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Gakh
authors.forename: Sungjo
authors.initials: S
authors.lastname: Park
authors.forename: Ulf
authors.initials: U
authors.lastname: Ryde
authors.forename: Martin
authors.initials: M
authors.lastname: Lindahl
authors.forename: Kirstin
authors.initials: K
authors.lastname: Leath
authors.forename: Elspeth
authors.initials: E
authors.lastname: Garman
authors.forename: Grazia
authors.initials: G
authors.lastname: Isaya
authors.forename: Salam
authors.initials: S
authors.lastname: Al-Karadaghi
mesh_terms: D000595:Amino Acid Sequence; D001692:Biological Transport; D018360:Crystallography, X-Ray; D007501:Iron / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008854:Microscopy, Electron; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000096923:Frataxin
chemical_list: D007501:Iron; D033862:Iron-Binding Proteins; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D000096923:Frataxin