Physiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide-processing functions of ferredoxin-2 and frataxin.
Carbon-Sulfur Lyases
/ metabolism
Ferredoxins
/ isolation & purification
Friedreich Ataxia
/ pathology
Iron
/ metabolism
Iron-Binding Proteins
/ isolation & purification
Iron-Sulfur Proteins
/ chemistry
Mutagenesis, Site-Directed
Nuclear Magnetic Resonance, Biomolecular
Oxidation-Reduction
Proton Magnetic Resonance Spectroscopy
Recombinant Proteins
/ genetics
Sulfides
/ metabolism
Zinc
/ metabolism
Frataxin
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 08 2019
08 08 2019
Historique:
received:
14
02
2019
accepted:
04
07
2019
entrez:
10
8
2019
pubmed:
10
8
2019
medline:
8
1
2020
Statut:
epublish
Résumé
Iron-sulfur (Fe-S) clusters are essential protein cofactors whose biosynthetic defects lead to severe diseases among which is Friedreich's ataxia caused by impaired expression of frataxin (FXN). Fe-S clusters are biosynthesized on the scaffold protein ISCU, with cysteine desulfurase NFS1 providing sulfur as persulfide and ferredoxin FDX2 supplying electrons, in a process stimulated by FXN but not clearly understood. Here, we report the breakdown of this process, made possible by removing a zinc ion in ISCU that hinders iron insertion and promotes non-physiological Fe-S cluster synthesis from free sulfide in vitro. By binding zinc-free ISCU, iron drives persulfide uptake from NFS1 and allows persulfide reduction into sulfide by FDX2, thereby coordinating sulfide production with its availability to generate Fe-S clusters. FXN stimulates the whole process by accelerating persulfide transfer. We propose that this reconstitution recapitulates physiological conditions which provides a model for Fe-S cluster biosynthesis, clarifies the roles of FDX2 and FXN and may help develop Friedreich's ataxia therapies.
Identifiants
pubmed: 31395877
doi: 10.1038/s41467-019-11470-9
pii: 10.1038/s41467-019-11470-9
pmc: PMC6687725
doi:
Substances chimiques
FDX2 protein, human
0
Ferredoxins
0
ISCU protein, human
0
Iron-Binding Proteins
0
Iron-Sulfur Proteins
0
IscU protein, mouse
0
Recombinant Proteins
0
Sulfides
0
persulfides
0
Iron
E1UOL152H7
Carbon-Sulfur Lyases
EC 4.4.-
NFS1 protein, human
EC 4.4.1.-
Nfs1 protein, mouse
EC 4.4.1.-
Zinc
J41CSQ7QDS
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3566Références
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