ArticleJournal of the American Chemical Society2022
Iron Insertion at the Assembly Site of the ISCU Scaffold Protein Is a Conserved Process Initiating Fe-S Cluster Biosynthesis.
Article in Journal of the American Chemical Society, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 37 citations in OpenAlex.
- Ferritinophagy Rewires Carnitine-Dependent Lipid Metabolism to Inhibit PRRSV and IAV Replication.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Intricacies in iron-sulfur cluster function and biogenesis: functional versatility, sulfur sources, and enzyme specificity.RSC chemical biology · 2026Review
- Regulatory networks of iron sulfur cluster biology in cancer mechanisms and therapeutic perspectives.iScience · 2026Review
- A Dinuclear Iron(II) Persulfide Complex Reacts with OJournal of the American Chemical Society · 2026Article
- Article
- Hydrogen sulfide acts as a sulfur source for iron sulfur cluster biosynthesis in cysteine desulfurase-deficientFrontiers in microbiology · 2026Article
- Ferroptosis is a novel pathogenic mechanism of FDXR-related disease via disruption of the NRF2 pathway.Cell death discovery · 2025Article
- Iron-sulfur cluster biogenesis and regulation of intracellular iron homeostasis in Escherichia coli.Metallomics : integrated biometal science · 2025Review
- How to build a [2Fe-2S] cluster.Nature chemical biology · 2025Article
- The ISC machinery assembles [2Fe-2S] clusters by formation and fusion of [1Fe-1S] precursors.Nature chemical biology · 2025Article
- Shedding Light on the Electron Delocalization Pathway at the [FeInorganic chemistry · 2025Article
- The human zinc-binding cysteine proteome.Cell · 2025Article
- Unraveling the molecular determinants of a rare human mitochondrial disorder caused by the P144L mutation of FDX2.Protein science : a publication of the Protein Society · 2024Article
- Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2.Nature communications · 2024Article
- Research progress of multi-enzyme complexes based on the design of scaffold protein.Bioresources and bioprocessing · 2023Review
- Structure of a putative immature form of a Rieske-type iron-sulfur protein in complex with zinc chloride.Communications chemistry · 2023Article
- Article
- The Glutathione System: A Journey from Cyanobacteria to Higher Eukaryotes.Antioxidants (Basel, Switzerland) · 2023Review
- Preparation of Iron-Based Sulfides and Their Applications in Biomedical Fields.Biomimetics (Basel, Switzerland) · 2023Review
- Article
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26 authors at 5 institutions in 4 countries.
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Abstract
Iron-sulfur (Fe-S) clusters are prosthetic groups of proteins biosynthesized on scaffold proteins by highly conserved multi-protein machineries. Biosynthesis of Fe-S clusters into the ISCU scaffold protein is initiated by ferrous iron insertion, followed by sulfur acquisition, via a still elusive mechanism. Notably, whether iron initially binds to the ISCU cysteine-rich assembly site or to a cysteine-less auxiliary site via N/O ligands remains unclear. We show here by SEC, circular dichroism (CD), and Mössbauer spectroscopies that iron binds to the assembly site of the monomeric form of prokaryotic and eukaryotic ISCU proteins via either one or two cysteines, referred to the 1-Cys and 2-Cys forms, respectively. The latter predominated at pH 8.0 and correlated with the Fe-S cluster assembly activity, whereas the former increased at a more acidic pH, together with free iron, suggesting that it constitutes an intermediate of the iron insertion process. Iron not binding to the assembly site was non-specifically bound to the aggregated ISCU, ruling out the existence of a structurally defined auxiliary site in ISCU. Characterization of the 2-Cys form by site-directed mutagenesis, CD, NMR, X-ray absorption, Mössbauer, and electron paramagnetic resonance spectroscopies showed that the iron center is coordinated by four strictly conserved amino acids of the assembly site, Cys35, Asp37, Cys61, and His103, in a tetrahedral geometry. The sulfur receptor Cys104 was at a very close distance and apparently bound to the iron center when His103 was missing, which may enable iron-dependent sulfur acquisition. Altogether, these data provide the structural basis to elucidate the Fe-S cluster assembly process and establish that the initiation of Fe-S cluster biosynthesis by insertion of a ferrous iron in the assembly site of ISCU is a conserved mechanism.
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