8rmg
Structure of the core ISC complex under turnover conditions (FDX2-bound in distal conformation)
Structural highlights
DiseaseNFS1_HUMAN Severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency. FunctionNFS1_HUMAN Catalyzes the removal of elemental sulfur from cysteine to produce alanine. It supplies the inorganic sulfur for iron-sulfur (Fe-S) clusters. May be involved in the biosynthesis of molybdenum cofactor.[1] Publication Abstract from PubMedIron-sulfur (FeS) protein biogenesis in eukaryotes begins with the de novo assembly of [2Fe-2S] clusters by the mitochondrial core iron-sulfur cluster assembly (ISC) complex. This complex comprises the scaffold protein ISCU2, the cysteine desulfurase subcomplex NFS1-ISD11-ACP1, the allosteric activator frataxin (FXN) and the electron donor ferredoxin-2 (FDX2). The structural interaction of FDX2 with the complex remains unclear. Here, we present cryo-EM structures of the human FDX2-bound core ISC complex showing that FDX2 and FXN compete for overlapping binding sites. FDX2 binds in either a 'distal' conformation, where its helix F interacts electrostatically with an arginine patch of NFS1, or a 'proximal' conformation, where this interaction tightens and the FDX2-specific C terminus binds to NFS1, facilitating the movement of the [2Fe-2S] cluster of FDX2 closer to the ISCU2 FeS cluster assembly site for rapid electron transfer. Structure-based mutational studies verify the contact areas of FDX2 within the core ISC complex. Two-stage binding of mitochondrial ferredoxin-2 to the core iron-sulfur cluster assembly complex.,Steinhilper R, Boss L, Freibert SA, Schulz V, Krapoth N, Kaltwasser S, Lill R, Murphy BJ Nat Commun. 2024 Dec 4;15(1):10559. doi: 10.1038/s41467-024-54585-4. PMID:39632806[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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