Abstract
Iron–sulfur (Fe–S) clusters are protein cofactors of a multitude of enzymes performing essential biological functions. Specialized multi-protein machineries present in all types of organisms support their biosynthesis. These machineries encompass a scaffold protein on which Fe–S clusters are assembled and a cysteine desulfurase that provides sulfur in the form of a persulfide. The sulfide ions are produced by reductive cleavage of the persulfide, which involves specific reductase systems. Several other components are required for Fe–S biosynthesis, including frataxin, a key protein of controversial function and accessory components for insertion of Fe–S clusters in client proteins. Fe–S cluster biosynthesis is thought to rely on concerted and carefully orchestrated processes. However, the elucidation of the mechanisms of their assembly has remained a challenging task due to the biochemical versatility of iron and sulfur and the relative instability of Fe–S clusters. Nonetheless, significant progresses have been achieved in the past years, using biochemical, spectroscopic and structural approaches with reconstituted system in vitro. In this paper, we review the most recent advances on the mechanism of assembly for the founding member of the Fe–S cluster family, the [2Fe2S] cluster that is the building block of all other Fe–S clusters. The aim is to provide a survey of the mechanisms of iron and sulfur insertion in the scaffold proteins by examining how these processes are coordinated, how sulfide is produced and how the dinuclear [2Fe2S] cluster is formed, keeping in mind the question of the physiological relevance of the reconstituted systems. We also cover the latest outcomes on the functional role of the controversial frataxin protein in Fe–S cluster biosynthesis.
Highlights
Iron–sulfur (Fe–S) clusters are small inorganic structures constituting the catalytic site of a multitude of enzymes
In the eukaryotic ISC machinery, Fe–S clusters are assembled on the ISCU scaffold, iron is provided to ISCU by a still ill-defined iron chaperone, sulfur is provided by the cysteine desulfurase complex NFS1–ISD11–acyl carrier proteins (ACP), and electrons are provided by FDX2 that is reduced by the NADPH-dependent ferredoxin reductase FDXR
This review focuses on the subset of proteins that ensure the biosynthesis of the [2Fe2S] cluster, with a special emphasis on the questions of the synchronization of iron and sulfur supplies to the scaffold proteins, how persulfide is reduced into sulfide and the mechanism of nucleation of iron and sulfide ions leading to formation of the dinuclear [2Fe2S] center
Summary
Iron–sulfur (Fe–S) clusters are small inorganic structures constituting the catalytic site of a multitude of enzymes. Maturation of Fe–S cluster proteins [13] These functions cover a transfer, redox catalysis, non-redox catalysis, binding and maturation of cluster wide range of biological roles, including ATP production, protein synthesis, oxidative-stress defense proteins [13]. In the eukaryotic ISC machinery, Fe–S clusters are assembled on the ISCU scaffold, iron is provided to ISCU by a still ill-defined iron chaperone, sulfur is provided by the cysteine desulfurase complex NFS1–ISD11–ACP, and electrons are provided by FDX2 that is reduced by the NADPH-dependent ferredoxin reductase FDXR. Combinations of biochemical, spectroscopic, structural and computational approaches with in vitro reconstituted machineries have significantly contributed to the understanding of the mechanism of Fe–S cluster assembly and the specific role of each component of these machineries Handling these reconstituted systems is a major challenge as reconstituted system can generate free sulfide, which contributes to Fe–S cluster formation in vitro. We review the latest data on the role of the frataxin protein, a key protein in the Fe–S cluster assembly process, the function of which has remained controversial until very recently
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