Towards a structural understanding of Friedreich’s ataxia: the solution structure of frataxin
Open accessAbstract
Background Lesions in the gene for frataxin, a nuclear-encoded mitochondrial protein, cause the recessively inherited condition Friedreich's ataxia. It is thought that the condition arises from disregulation of mitochondrial iron homeostasis, with concomitant oxidative damage leading to neuronal death. Very little is, as yet, known about the biochemical function of frataxin. Results Here, we show that the mature form of recombinant frataxin behaves in solution as a monodisperse species that is composed of a 15-residue-long unstructured N terminus and an evolutionarily conserved C-terminal region that is able to fold independently. The structure of the C-terminal domain consists of a stable seven-stranded antiparallel beta sheet packing against a pair of parallel helices. The structure is compact with neither grooves nor cavities, features that are typical of iron-binding modules. Exposed evolutionarily conserved residues cover a broad area and all cluster on the beta-sheet face of the structure, suggesting that this is a functionally important surface. The effect of two clinically occurring mutations on the fold was checked experimentally. When the mature protein was titrated with iron, no tendency to iron-binding or to aggregation was observed. Conclusions Knowledge of the frataxin structure provides important guidelines as to the nature of the frataxin binding partner. The absence of all the features expected for an iron-binding activity, the large conserved area on its surface and lack of evidence for iron-binding activity strongly support an indirect involvement of frataxin in iron metabolism. The effects of point mutations associated with Friedreich's ataxia can be rationalised by knowledge of the structure and suggest possible models for the occurrence of the disease in compound heterozygous patients.
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Hepcidin negatively regulates iron efflux by binding Fpn and triggering its internalization and subsequent degradation.
“It negatively regulates iron efflux by binding Fpn and triggering its internalization and subsequent degradation (215).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [215]
Fpn is posttranslationally regulated by the peptide hormone hepcidin.
“Fpn is posttranslationally regulated by a peptide hormone, hepcidin (215).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [215]
Overexpression of Fpn accelerates export of cytosolic iron.
“Over-expression of Fpn accelerates export of cytosolic iron (215)”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [215]
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- Authors
- Musco, G., Stier, G., Kolmerer, B., Adinolfi, S., Martin, S., Frenkiel, T., Gibson, T., & Pastore, A.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Corresponding author
- Pastore, Annalisa
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2000-07
- Volume
- 8
- Issue
- 7
- Pages
- 695-707
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2043666185
- Cited by
- 166
- References
- 53
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 9 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 3 · 2015: 6 · 2014: 11 · 2013: 9 · 2012: 3
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Scuola Normale Superiore di Pisa (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- Friedreich's ataxia, frataxin, protein solution structure, mitochondrial iron homeostasis, C-terminal domain, antiparallel beta-sheet, point mutations, compound heterozygosity, protein aggregation
- MeSH terms
- Frataxin, Amino Acid Sequence, Animals, Bacterial Proteins, Carrier Proteins, Circular Dichroism, Friedreich Ataxia, Fungal Proteins, Heterozygote, Humans, Iron, Ligands, Mitochondria, Models, Molecular, Molecular Sequence Data, Plant Proteins, Protein Conformation, Recombinant Fusion Proteins, Species Specificity, Structure-Activity Relationship, Helminth Proteins, Sequence Alignment, Point Mutation, Sequence Homology, Amino Acid, Protein Structure, Secondary, Phosphotransferases (Alcohol Group Acceptor), Oxidative Stress, Evolution, Molecular, Iron-Binding Proteins, Transferrin-Binding Proteins, Mice
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