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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.

Original publication

DOI

10.1016/j.str.2006.08.010

Type

Journal article

Journal

Structure

Publication Date

10/2006

Volume

14

Pages

1535 - 1546

Keywords

Amino Acid Sequence, Biological Transport, Crystallography, X-Ray, Iron, Iron-Binding Proteins, Microscopy, Electron, Mitochondrial Proteins, Models, Molecular, Molecular Sequence Data, Mutation, Protein Binding, Protein Conformation, Saccharomyces cerevisiae Proteins