ArticleProceedings of the National Academy of Sciences of the United States of America2019
Mechanism of activation of the human cysteine desulfurase complex by frataxin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 91 citations in OpenAlex.
- Article
- D-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1.Nature metabolism · 2025Article
- Rust and redemption: iron-sulfur clusters and oxygen in human disease and health.Metallomics : integrated biometal science · 2025Review
- Frataxin: from the sequence to the biological role.Biophysical reviews · 2025Review
- Identification of a Selective Inhibitor of Human NFS1, a Cysteine Desulfurase Involved in Fe-S Cluster Assembly, via Structure-Based Virtual Screening.International journal of molecular sciences · 2025Article
- Frataxin Traps Low Abundance Quaternary Structure to Stimulate Human Fe-S Cluster Biosynthesis.Biochemistry · 2025Article
- The human zinc-binding cysteine proteome.Cell · 2025Article
- Friedreich ataxia: what can we learn from non-GAA repeat mutations?Neurodegenerative disease management · 2025Review
- Impaired Iron-Sulfur Cluster Synthesis Induces Mitochondrial PARthanatos in Diabetic Cardiomyopathy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy.Communications biology · 2024Article
- Persulfide Transfer to SufE Activates the Half-Sites Reactivity of theBiochemistry · 2024Article
- Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2.Nature communications · 2024Article
- Targeting mitochondrial bioenergetics by combination treatment with imatinib and dichloroacetate in human erythroleukemic K‑562 and colorectal HCT‑116 cancer cells.International journal of oncology · 2024Article
- HCells · 2024Article
- Searching for Frataxin Function: Exploring the Analogy with Nqo15, the Frataxin-like Protein of Respiratory Complex I fromInternational journal of molecular sciences · 2024Article
- METTL17 is an Fe-S cluster checkpoint for mitochondrial translation.Molecular cell · 2024Article
- A kinetic model of iron trafficking in growing Saccharomyces cerevisiae cells; applying mathematical methods to minimize the problem of sparse data and generate viable autoregulatory mechanisms.PLoS computational biology · 2023Article
- Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich's Ataxia Cells.International journal of molecular sciences · 2023Article
- Structural Plasticity of NFU1 Upon Interaction with Binding Partners: Insights into the Mitochondrial [4Fe-4S] Cluster Pathway.Journal of molecular biology · 2023Article
- Roles of conserved active site residues in the IscS cysteine desulfurase reaction.Frontiers in microbiology · 2023Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The function of frataxin (FXN) has garnered great scientific interest since its depletion was linked to the incurable neurodegenerative disease Friedreich's ataxia (FRDA). FXN has been shown to be necessary for iron-sulfur (Fe-S) cluster biosynthesis and proper mitochondrial function. The structural and functional core of the Fe-S cluster assembly complex is a low-activity pyridoxal 5'-phosphate (PLP)-dependent cysteine desulfurase enzyme that consists of catalytic (NFS1), LYRM protein (ISD11), and acyl carrier protein (ACP) subunits. Although previous studies show that FXN stimulates the activity of this assembly complex, the mechanism of FXN activation is poorly understood. Here, we develop a radiolabeling assay and use stopped-flow kinetics to establish that FXN is functionally linked to the mobile S-transfer loop cysteine of NFS1. Our results support key roles for this essential cysteine residue in substrate binding, as a general acid to advance the Cys-quinonoid PLP intermediate, as a nucleophile to form an NFS1 persulfide, and as a sulfur delivery agent to generate a persulfide species on the Fe-S scaffold protein ISCU2. FXN specifically accelerates each of these individual steps in the mechanism. Our resulting architectural switch model explains why the human Fe-S assembly system has low inherent activity and requires activation, the connection between the functional mobile S-transfer loop cysteine and FXN binding, and why the prokaryotic system does not require a similar FXN-based activation. Together, these results provide mechanistic insights into the allosteric-activator role of FXN and suggest new strategies to replace FXN function in the treatment of FRDA.
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