The Structures of Frataxin Oligomers Reveal the Mechanism for the Delivery and Detoxification of Iron

Tobias Karlberg, Ulrika Schagerlöf, Oleksandr Gakh, Sungjo Park, Ulf Ryde, Martin Lindahl, Kirstin Leath, Elspeth Garman, Grazia Isaya, Salam Al-Karadaghi

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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.

Original languageEnglish (US)
Pages (from-to)1535-1546
Number of pages12
JournalStructure
Volume14
Issue number10
DOIs
StatePublished - Oct 2006

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Keywords

  • MOLNEURO

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Karlberg, T., Schagerlöf, U., Gakh, O., Park, S., Ryde, U., Lindahl, M., Leath, K., Garman, E., Isaya, G., & Al-Karadaghi, S. (2006). The Structures of Frataxin Oligomers Reveal the Mechanism for the Delivery and Detoxification of Iron. Structure, 14(10), 1535-1546. https://doi.org/10.1016/j.str.2006.08.010