Article

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

Department of Molecular Biophysics, Center for Chemistry and Chemical Engineering, Lund University, P.O. Box 124, SE-221 00 Lund, Sweden.
Structure (Impact Factor: 6.79). 11/2006; 14(10):1535-46. DOI: 10.1016/j.str.2006.08.010
Source: PubMed

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.

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Available from: Salam Al-Karadaghi, Aug 28, 2015
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    • "Interestingly, the equivalent region in Yfh1 seems more rigid. In the X-ray structure, the region is visible and involved in intermolecular interactions with other copies of the molecule (Karlberg et al. 2006). In the solution structure, it bends back in a conformation that is shared by all copies of the NMR bundle, whereas it should adopt different conformations in different models if it were flexible (He et al. 2004). "
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    ABSTRACT: Reduced levels of the protein frataxin cause the neurodegenerative disease Friedreich's ataxia. Pathology is associated with disruption of iron–sulfur cluster biosynthesis, mitochondrial iron overload, and oxidative stress. Frataxin is a highly conserved iron-binding protein present in most organisms. Despite the intense interest generated since the determination of its pathology, identification of the cellular function of frataxin has so far remained elusive. In this review, we revisit the most significant milestones that have led us to our current understanding of frataxin and its functions. The picture that emerges is that frataxin is a crucial element of one of the most essential cellular machines specialized in iron-sulfur cluster biogenesis. Future developments, therefore, can be expected from further advancements in our comprehension of this machine.
    Journal of Neurochemistry 08/2013; 126(s1). DOI:10.1111/jnc.12220 · 4.24 Impact Factor
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    • "Seven mutations were directed against acidic residues from the acidic ridge of frataxin (E96K, D104G, E108K, E111K, D115K, D122Y and D124K). One mutation, Y95G, was proposed to stabilize the trimeric structure in yeast frataxin [26]. All mutations involved residues exposed on the protein surface except Y95, I154 and W173, for which side chains are mostly buried in the protein core (Fig 3B). "
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    ABSTRACT: Frataxin, the mitochondrial protein deficient in Friedreich ataxia, a rare autosomal recessive neurodegenerative disorder, is thought to be involved in multiple iron-dependent mitochondrial pathways. In particular, frataxin plays an important role in the formation of iron-sulfur (Fe-S) clusters biogenesis. We present data providing new insights into the interactions of mammalian frataxin with the Fe-S assembly complex by combining in vitro and in vivo approaches. Through immunoprecipitation experiments, we show that the main endogenous interactors of a recombinant mature human frataxin are ISCU, NFS1 and ISD11, the components of the core Fe-S assembly complex. Furthermore, using a heterologous expression system, we demonstrate that mammalian frataxin interacts with the preformed core complex, rather than with the individual components. The quaternary complex can be isolated in a stable form and has a molecular mass of ≈190 kDa. Finally, we demonstrate that the mature human FXN(81-210) form of frataxin is the essential functional form in vivo. Our results suggest that the interaction of frataxin with the core ISCU/NFS1/ISD11 complex most likely defines the essential function of frataxin. Our results provide new elements important for further understanding the early steps of de novo Fe-S cluster biosynthesis.
    PLoS ONE 01/2011; 6(1):e16199. DOI:10.1371/journal.pone.0016199 · 3.23 Impact Factor
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    • "It remains to be elucidated, however, how frataxin protects from revertant mutations in our prokaryotic model. This effect can be explained by increased effectiveness of DNA damage repair due to increased ISC formation, but could also be interpreted to be caused by ferroxidase and/or iron-detoxification activity of frataxin which then would protect the DNA from oxidative damage, as suggested previously [6,7]. "
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    ABSTRACT: DNA-repair mechanisms enable cells to maintain their genetic information by protecting it from mutations that may cause malignant growth. Recent evidence suggests that specific DNA-repair enzymes contain ISCs (iron-sulfur clusters). The nuclearencoded protein frataxin is essential for the mitochondrial biosynthesis of ISCs. Frataxin deficiency causes a neurodegenerative disorder named Friedreich's ataxia in humans. Various types of cancer occurring at young age are associated with this disease, and hence with frataxin deficiency. Mice carrying a hepatocyte-specific disruption of the frataxin gene develop multiple liver tumours for unresolved reasons. In the present study, we show that frataxin deficiency in murine liver is associated with increased basal levels of oxidative DNA base damage. Accordingly, eukaryotic V79 fibroblasts overexpressing human frataxin show decreased basal levels of these modifications, while prokaryotic Salmonella enterica serotype Typhimurium TA104 strains transformed with human frataxin show decreased mutation rates. The repair rates of oxidative DNA base modifications in V79 cells overexpressing frataxin were significantly higher than in control cells. Lastly, cleavage activity related to the ISC-independent repair enzyme 8-oxoguanine glycosylase was found to be unaltered by frataxin overexpression. These findings indicate that frataxin modulates DNA-repair mechanisms probably due to its impact on ISC-dependent repair proteins, linking mitochondrial dysfunction to DNA repair and tumour initiation.
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