The structures of frataxin oligomers reveal the mechanism for the delivery and detoxification of iron.
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.
Karlberg
Tobias
T
Department of Molecular Biophysics, Center for Chemistry and Chemical Engineering, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden.
Schagerlöf
Ulrika
U
Gakh
Oleksandr
O
Park
Sungjo
S
Ryde
Ulf
U
Lindahl
Martin
M
Leath
Kirstin
K
Garman
Elspeth
E
Isaya
Grazia
G
Al-Karadaghi
Salam
S
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
D007501:Iron; D033862:Iron-Binding Proteins; D024101:Mitochondrial Proteins; D029701:Saccharomyces cerevisiae Proteins; D000096923:Frataxin