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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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“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]
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“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]
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“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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Self-citationThe NMR contribution to protein–protein networking in Fe–S protein maturation
Banci, L., Camponeschi, F., Ciofi‐Baffoni, S., & Piccioli, M. (2018) · JBIC Journal of Biological Inorganic Chemistry · doi:10.1007/s00775-018-1552-x · Cited by 46
Huang, J., Dizin, E., & Cowan, J. A. (2008) · JBIC Journal of Biological Inorganic Chemistry · doi:10.1007/s00775-008-0369-4 · Cited by 45
Correia, A. R., Adinolfi, S., Pastore, A., & Gomes, C. M. (2006) · Biochemical Journal · doi:10.1042/bj20060345 · Cited by 45
Self-citationFriedreich Ataxia: Detection of GAA Repeat Expansions and Frataxin Point Mutations
Pandolfo, M. (2006) · Humana Press eBooks · doi:10.1385/1-59745-088-x:197 · Cited by 44
Frataxin interacts with Isu1 through a conserved tryptophan in its β-sheet
Leidgens, S., Smet, S. D., & Foury, F. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp495 · Cited by 44
Crack, J. C., Balasiny, B. K., Bennett, S. P., Rolfe, M. D., Froes, A. V. T. D. V., MacMillan, F., Green, J. D., Cole, J. A., & Brun, N. E. L. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.1c12407 · Cited by 42
Monfort, B., Want, K., Gervason, S., & D’Autréaux, B. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.838335 · Cited by 42
Yoon, T., Dizin, E., & Cowan, J. A. (2007) · JBIC Journal of Biological Inorganic Chemistry · doi:10.1007/s00775-007-0205-2 · Cited by 41
Correia, A. R., Wang, T., Craig, E. A., & Gomes, C. M. (2009) · Biochemical Journal · doi:10.1042/bj20091612 · Cited by 43
“other putative functional region of the protein, believed to be involved in the binding of frataxin to its protein partners [23, 29 ].”
BackgroundKim, J. H., Bothe, J. R., Alderson, T. R., & Markley, J. L. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.11.020 · Cited by 38
Prischi, F., Pastore, C., Carroni, M., Iannuzzi, C., Adinolfi, S., Temussi, P., & Pastore, A. (2010) · Protein Expression and Purification · doi:10.1016/j.pep.2010.05.003 · Cited by 37
Self-citationFunctional studies of frataxin
Isaya, G., O'Neill, H., Gakh, O., Park, S., Mantcheva, R., & Mooney, S. (2004) · Acta Paediatrica · doi:10.1111/j.1651-2227.2004.tb03061.x · Cited by 37
“The threedimensional structure of human frataxin has revealed a highly conserved negatively charged surface, similar to the anionic surface involved in the iron storage mechanism of ferritin (40, 41).”
BackgroundAdinolfi, S., Puglisi, R., Crack, J. C., Iannuzzi, C., Piaz, F. D., Konarev, P. V., Svergun, D. I., Martin, S. R., Brun, N. E. L., & Pastore, A. (2018) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2017.00097 · Cited by 34
“The proteins were purified as previously described (Musco et al., 2000; Pastore et al., 2006) by affinity chromatography using Ni-NTA agarose gel and cleaved from the His-GST tag by Tobacco virus protease (TEV) protease.”
MethodSelf-citationLi, N., Sickmier, E. A., Zhang, R., Joachimiak, A., & White, S. W. (2002) · Molecular Microbiology · doi:10.1046/j.1365-2958.2002.02809.x · Cited by 34
“This domain contains an antiparallel b-sheet and a-helices packed onto one side (Musco et al., 2000) with a topology identical to that of MotCF, but it lacks the equivalent of the b5-a2 segment.”
BackgroundTurowski, V. R., Aknin, C., Maliandi, M. V., Buchensky, C., Leaden, L., Peralta, D. A., Busi, M. V., Araya, A., & Gomez‐Casati, D. F. (2015) · PLoS ONE · doi:10.1371/journal.pone.0141443 · Cited by 33
Rufini, A., Cavallo, F., Condò, I., Fortuni, S., Martino, G. D., Incani, O., Venere, A. D., Benini, M., Massaro, D. S., Arcuri, G., et al. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.12.011 · Cited by 34
Blauenburg, B., Mielcarek, A., Altegoer, F., Fage, C. D., Linne, U., Bange, G., & Marahiel, M. A. (2016) · PLoS ONE · doi:10.1371/journal.pone.0158749 · Cited by 33
“coli frataxin (PDB ID 3S4M, 2GA5, and 2EFF, respectively) assume an α/β fold in which two α-helices are stacked against a 6-stranded β-sheet, with the N-terminal α-helix harboring several acidic residues (the ‘acidic ridge’) [21].”
BackgroundDoni, D., Cavion, F., Bortolus, M., Baschiera, E., Muccioli, S., Tombesi, G., d’Ettorre, F., Ottaviani, D., Marchesan, E., Leanza, L., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06320-y · Cited by 32
“We have previously found that in healthy cells frataxin, despite being a soluble protein lacking transmembrane domains [40, 41], is closely attached to the mitochondrial inner membrane and enriched in the cristae [42], which contain both the FeS cluster assembly machinery [42, 43] and the…”
Iron chaperones for mitochondrial Fe–S cluster biosynthesis and ferritin iron storage
Subramanian, P., Rodrigues, A. V., Ghimire-Rijal, S., & Stemmler, T. L. (2011) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2011.01.003 · Cited by 31
Protein Stability and Dynamics Modulation: The Case of Human Frataxin
Román, E. A., Faraj, S. E., Gallo, M. L., Salvay, A. G., Ferreiro, D. U., & Santos, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045743 · Cited by 31
“The NMR proton spectrum of the full length hFXN shows a high-quality peak dispersion (Figure 3A), evidence of the globular and stable native conformation of the wild-type protein [27].”
BackgroundPathophysiogical and therapeutic progress in Friedreich ataxia
Puccio, H. M., Anheim, M., & Tranchant, C. (2014) · Revue Neurologique · doi:10.1016/j.neurol.2014.03.008 · Cited by 31
“[40] Musco G, Stier G, Kolmerer B, Adinolfi S, Martin S, Frenkiel T, et al.”
BackgroundFaraj, S. E., Román, E. A., Arán, M., Gallo, M. L., & Santos, J. (2014) · FEBS Journal · doi:10.1111/febs.12869 · Cited by 29
Clinical use of frataxin measurement in a patient with a novel deletion in the FXN gene
Saccà, F., Marsili, A., Puorro, G., Antenora, A., Pane, C., Tessa, A., Scoppettuolo, P., Nesti, C., Morra, V. B., Michele, G. D., et al. (2012) · Journal of Neurology · doi:10.1007/s00415-012-6770-5 · Cited by 28
“Nevertheless, three-dimensional models of frataxin have shown that the hydrophobic side chains of Leu-198, Leu-200 and Leu-203, all truncated in our patient, are essential for frataxin stability [16, 17].”
BackgroundSmith, F. M., & Kosman, D. J. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.569293 · Cited by 27
Variation in protein Cα‐related one‐bond J couplings
Schmidt, J. M., Howard, M. J., Maestre-Martínez, M., Pérez, C., & Löhr, F. (2008) · Magnetic Resonance in Chemistry · doi:10.1002/mrc.2337 · Cited by 27
His86 from the N-Terminus of Frataxin Coordinates Iron and Is Required for Fe–S Cluster Synthesis
Gentry, L. E., Thacker, M. A., Doughty, R., Timkovich, R., & Busenlehner, L. S. (2013) · Biochemistry · doi:10.1021/bi400443n · Cited by 26
Pandolfo, M. (2011) · Handbook of clinical neurology · doi:10.1016/b978-0-444-51892-7.00017-6 · Cited by 26
Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › 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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