Iron –sulfur cluster biogenesis in mammalian cells: New insights into the molecular mechanisms of cluster delivery

Abstract

Iron-sulfur (Fe-S) clusters are ancient, ubiquitous cofactors composed of iron and inorganic sulfur. The combination of the chemical reactivity of iron and sulfur, together with many variations of cluster composition, oxidation states and protein environments, enables Fe-S clusters to participate in numerous biological processes. Fe-S clusters are essential to redox catalysis in nitrogen fixation, mitochondrial respiration and photosynthesis, to regulatory sensing in key metabolic pathways (i. e. cellular iron homeostasis and oxidative stress response), and to the replication and maintenance of the nuclear genome. Fe-S cluster biogenesis is a multistep process that involves a complex sequence of catalyzed protein- protein interactions and coupled conformational changes between the components of several dedicated multimeric complexes. Intensive studies of the assembly process have clarified key points in the biogenesis of Fe-S proteins. However several critical questions still remain, such as: what is the role of frataxin? Why do some defects of Fe-S cluster biogenesis cause mitochondrial iron overload? How are specific Fe-S recipient proteins recognized in the process of Fe-S transfer? This review focuses on the basic steps of Fe-S cluster biogenesis, drawing attention to recent advances achieved on the identification of molecular features that guide selection of specific subsets of nascent Fe-S recipients by the cochaperone HSC20. Additionally, it outlines the distinctive phenotypes of human diseases due to mutations in the components of the basic pathway.

Architecture of the Yeast Mitochondrial Iron-Sulfur Cluster Assembly Machinery

“…However, a protein docking study further suggested that Yfh1 binding would only be possible with the flexible loop of Nfs1 positioned inside the cysteine substrate-binding site rather than in proximity of the Fe-S cluster assembly site. This implies that iron and sulfur donation would have to occur sequentially and that sulfur donation would require the displacement of Yfh1 from the Fe-S cluster assembly complex (17), which is in contrast with the general consensus that Fe-S cluster assembly requires the simultaneous binding of the scaffold to both the cysteine desulfurase and the iron donor (1,2).…”

“…In yeast and animal cells, mitochondria assemble Fe-S clusters autonomously, whereas other cellular compartments depend on precursors and/or signals generated by mitochondria (2). A complete loss of mitochondrial Fe-S cluster synthesis is therefore lethal, while partial defects typically result in mitochondrial dysfunction, multiple Fe-S enzyme deficits throughout the cell, and global iron imbalance (1). In humans, inherited defects in mitochondrial Fe-S cluster synthesis have been linked to the neurodegenerative disease Friedreich ataxia and to various tissue-specific conditions, although the role of this process in human disease is most likely underestimated (3).…”

“…Fe-S clusters are highly versatile cofactors that both prokaryotic and eukaryotic cells utilize in many essential metabolic pathways (1). In yeast and animal cells, mitochondria assemble Fe-S clusters autonomously, whereas other cellular compartments depend on precursors and/or signals generated by mitochondria (2).…”

Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery

“…1-2, and b, pp. [1][2][3][4][5][6][7][8], or between monomers from two adjacent trimers (supplemental Table S2 24 complex. A-F, to visualize the structure of the entire complex, the simulated half of the structure was aligned with itself into the EM density map of the refined 3D model.…”

Why Studying Rare Diseases Is So Important: Do You Know of This Disease?

“…But these clusters do not pre-exist and are not produced for free. To produce them, we need specialized machines in our bodies, which are made of several different proteins, much like an assembly line [6]. Frataxin seems to be an important part of this assembly line [7,8].…”