8PK9
Structure of the human mitochondrial iron-sulfur cluster biosynthesis complex during persulfide transfer (persulfide on NFS1 and ISCU2)
Summary for 8PK9
| Entry DOI | 10.2210/pdb8pk9/pdb |
| EMDB information | 17733 |
| Descriptor | Cysteine desulfurase, LYR motif-containing protein 4, Acyl carrier protein, ... (9 entities in total) |
| Functional Keywords | cysteine desulfurase, fes biosynthesis, fes biogenesis, mitochondria, friedreich's ataxia, persulfide, frataxin, transferase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 98232.16 |
| Authors | |
| Primary citation | Schulz, V.,Steinhilper, R.,Oltmanns, J.,Freibert, S.A.,Krapoth, N.,Linne, U.,Welsch, S.,Hoock, M.H.,Schunemann, V.,Murphy, B.J.,Lill, R. Mechanism and structural dynamics of sulfur transfer during de novo [2Fe-2S] cluster assembly on ISCU2. Nat Commun, 15:3269-3269, 2024 Cited by PubMed 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 Cys381 to Cys138 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 Cys138 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. PubMed: 38627381DOI: 10.1038/s41467-024-47310-8 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.58 Å) |
Structure validation
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