Mammalian Frataxin Controls Sulfur Production and Iron Entry during de Novo Fe 4 S 4 Cluster Assembly
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Iron-sulfur (Fe-S) cluster-containing proteins are essential components of cells. In eukaryotes, Fe-S clusters are synthesized by the mitochondrial iron-sulfur cluster (ISC) machinery and the cytosolic iron-sulfur assembly (CIA) system. In the mammalian ISC machinery, preassembly of the Fe-S cluster on the scaffold protein (ISCU) involves a cysteine desulfurase complex (NFS1/ISD11) and frataxin (FXN), the protein deficient in Friedreich's ataxia. Here, by comparing the biochemical and spectroscopic properties of quaternary (ISCU/NFS1/ISD11/FXN) and ternary (ISCU/NFS1/ISD11) complexes, we show that FXN stabilizes the quaternary complex and controls iron entry to the complex through activation of cysteine desulfurization. Furthermore, we show for the first time that in the presence of iron and L-cysteine, an [Fe(4)S(4)] cluster is formed within the quaternary complex that can be transferred to mammalian aconitase (mACO2) to generate an active enzyme. In the absence of FXN, although the ternary complex can assemble an Fe-S cluster, the cluster is inefficiently transferred to ACO2. Taken together, these data help to unravel further the Fe-S cluster assembly process and the molecular basis of Friedreich's ataxia.
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Frataxin has been identified as an important iron regulator of Fe-S biogenesis.
“The Fe source of the cluster is not yet known, although frataxin (FXN) has been identified as an important iron regulator of Fe-S biogenesis (Colin et al., 2013).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Colin et al., 2013
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The Role of Iron Regulation in Immunometabolism and Immune-Related Disease
Cronin, S. J. F., Woolf, C. J., Weiss, G., & Penninger, J. M. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00116 · Cited by 299 · see citing works
- Authors
- Colin, F., Martelli, A., Clémancey, M., Latour, J.-M., Gambarelli, S., Zeppieri, L., Birck, C., Page, A., Puccio, H., & Ollagnier de Choudens, S.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Université Joseph Fourier (FR)
- DSV/iRTSV/CBM, UMR 5249 CEA-Université Grenoble I-CNRS/Equipe Biocatalyse, CEA-Grenoble, 17 Rue des Martyrs, 38054 Grenoble Cedex 09, France
- Corresponding author
- Puccio, Hélène
- ORCID
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-01-07
- Volume
- 135
- Issue
- 2
- Pages
- 733-740
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2065331957
- Cited by
- 148
- References
- 48
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 12 · 2023: 2 · 2022: 13 · 2021: 11 · 2020: 6 · 2019: 16 · 2018: 19 · 2017: 14 · 2016: 7 · 2015: 13 · 2014: 19 · 2013: 10
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- other-oa
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Topics
- Physical Sciences › Energy › Renewable Energy, Sustainability and the Environment › Metalloenzymes and iron-sulfur proteins
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- frataxin, iron-sulfur cluster assembly, Friedreich's ataxia, IscU, cysteine desulfurase, sulfur production, aconitase
- MeSH terms
- Frataxin, Animals, Humans, Iron, Iron-Sulfur Proteins, Models, Molecular, Sulfur, Iron-Binding Proteins, Coordination Complexes
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