Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2

Vinzent Schulz, Ralf Steinhilper, Jonathan Oltmanns, Sven-A. Freibert, Nils Krapoth, Uwe Linne, Sonja Welsch, Maren H. Hoock, Volker Schünemann, Bonnie J. Murphy () and Roland Lill ()
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Vinzent Schulz: Institut für Zytobiologie, Philipps-Universität Marburg
Ralf Steinhilper: Redox and Metalloprotein Research Group, Max Planck Institute of Biophysics
Jonathan Oltmanns: Department of Physics, Biophysics and Medical Physics, University of Kaiserslautern-Landau
Sven-A. Freibert: Institut für Zytobiologie, Philipps-Universität Marburg
Nils Krapoth: Institut für Zytobiologie, Philipps-Universität Marburg
Uwe Linne: Mass Spectrometry Facility of the Department of Chemistry, Philipps-Universität Marburg
Sonja Welsch: Max Planck Institute of Biophysics
Maren H. Hoock: Department of Physics, Biophysics and Medical Physics, University of Kaiserslautern-Landau
Volker Schünemann: Department of Physics, Biophysics and Medical Physics, University of Kaiserslautern-Landau
Bonnie J. Murphy: Redox and Metalloprotein Research Group, Max Planck Institute of Biophysics
Roland Lill: Institut für Zytobiologie, Philipps-Universität Marburg

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Maturation of iron-sulfur proteins in eukaryotes is initiated in mitochondria by the core iron-sulfur cluster assembly (ISC) complex, consisting of the cysteine desulfurase sub-complex NFS1-ISD11-ACP1, the scaffold protein ISCU2, the electron donor ferredoxin FDX2, and frataxin, a protein dysfunctional in Friedreich’s ataxia. The core ISC complex synthesizes [2Fe-2S] clusters de novo from Fe and a persulfide (SSH) bound at conserved cluster assembly site residues. Here, we elucidate the poorly understood Fe-dependent mechanism of persulfide transfer from cysteine desulfurase NFS1 to ISCU2. High-resolution cryo-EM structures obtained from anaerobically prepared samples provide snapshots that both visualize different stages of persulfide transfer from Cys381NFS1 to Cys138ISCU2 and clarify the molecular role of frataxin in optimally positioning assembly site residues for fast sulfur transfer. Biochemical analyses assign ISCU2 residues essential for sulfur transfer, and reveal that Cys138ISCU2 rapidly receives the persulfide without a detectable intermediate. Mössbauer spectroscopy assessing the Fe coordination of various sulfur transfer intermediates shows a dynamic equilibrium between pre- and post-sulfur-transfer states shifted by frataxin. Collectively, our study defines crucial mechanistic stages of physiological [2Fe-2S] cluster assembly and clarifies frataxin’s molecular role in this fundamental process.

Date: 2024
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DOI: 10.1038/s41467-024-47310-8

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