ArticleBiochemistry2011
Friedreich's ataxia variants I154F and W155R diminish frataxin-based activation of the iron-sulfur cluster assembly complex.
Article in Biochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 58 citations in OpenAlex.
- Partial bypass of frataxin deficiency by ISCU M141I restores cytosolic and nuclear Fe-S cluster assembly.Cell death and differentiation · 2026Article
- Pathological frataxin deficiency in mice causes tissue-specific alterations in iron homeostasis.iScience · 2026Article
- Comparative Structural Analysis of Escherichia Coli Cyay at Room and Cryogenic Temperatures Using Macromolecular and Serial Crystallography.Chembiochem : a European journal of chemical biology · 2025Article
- Frataxin Traps Low Abundance Quaternary Structure to Stimulate Human Fe-S Cluster Biosynthesis.Biochemistry · 2025Article
- An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich's Ataxia.International journal of molecular sciences · 2024Article
- Phenotypic variation of FXN compound heterozygotes in a Friedreich ataxia cohort.Annals of clinical and translational neurology · 2024Article
- Searching for Frataxin Function: Exploring the Analogy with Nqo15, the Frataxin-like Protein of Respiratory Complex I fromInternational journal of molecular sciences · 2024Article
- Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations.Cellular and molecular life sciences : CMLS · 2022Article
- Molecular Details of the Frataxin-Scaffold Interaction during Mitochondrial Fe-S Cluster Assembly.International journal of molecular sciences · 2021Review
- Mechanism of activation of the human cysteine desulfurase complex by frataxin.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Mechanism of frataxin "bypass" in human iron-sulfur cluster biosynthesis with implications for Friedreich's ataxia.The Journal of biological chemistry · 2019Article
- Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism.Nature communications · 2019Article
- Identification of a novel missense mutation in Friedreich's ataxia -FXNAnnals of clinical and translational neurology · 2019Article
- Impact ofInternational journal of molecular sciences · 2018Review
- Biophysical characterisation of the recombinant human frataxin precursor.FEBS open bio · 2018Article
- Robust Production, Crystallization, Structure Determination, and Analysis of [Fe-S] Proteins: Uncovering Control of Electron Shuttling and Gating in the Respiratory Metabolism of Molybdopterin Guanine Dinucleotide Enzymes.Methods in enzymology · 2018Article
- Selected missense mutations impair frataxin processing in Friedreich ataxia.Annals of clinical and translational neurology · 2017Article
- Mitochondrial Cysteine Desulfurase and ISD11 Coexpressed in Escherichia coli Yield Complex Containing Acyl Carrier Protein.ACS chemical biology · 2017Article
- Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery.The Journal of biological chemistry · 2016Article
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3 authors.
Funding
Abstract
Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease that has been linked to defects in the protein frataxin (Fxn). Most FRDA patients have a GAA expansion in the first intron of their Fxn gene that decreases protein expression. Some FRDA patients have a GAA expansion on one allele and a missense mutation on the other allele. Few functional details are known for the ∼15 different missense mutations identified in FRDA patients. Here in vitro evidence is presented that indicates the FRDA I154F and W155R variants bind more weakly to the complex of Nfs1, Isd11, and Isu2 and thereby are defective in forming the four-component SDUF complex that constitutes the core of the Fe-S cluster assembly machine. The binding affinities follow the trend Fxn ∼ I154F > W155F > W155A ∼ W155R. The Fxn variants also have diminished ability to function as part of the SDUF complex to stimulate the cysteine desulfurase reaction and facilitate Fe-S cluster assembly. Four crystal structures, including the first for a FRDA variant, reveal specific rearrangements associated with the loss of function and lead to a model for Fxn-based activation of the Fe-S cluster assembly complex. Importantly, the weaker binding and lower activity for FRDA variants correlate with the severity of disease progression. Together, these results suggest that Fxn facilitates sulfur transfer from Nfs1 to Isu2 and that these in vitro assays are sensitive and appropriate for deciphering functional defects and mechanistic details for human Fe-S cluster biosynthesis.
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