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Review
. 2019 Jun;32(3):343-353.
doi: 10.1007/s10534-019-00191-7. Epub 2019 Mar 28.

The indispensable role of mammalian iron sulfur proteins in function and regulation of multiple diverse metabolic pathways

Tracey A Rouault  1
Affiliations
Review

The indispensable role of mammalian iron sulfur proteins in function and regulation of multiple diverse metabolic pathways

Tracey A Rouault. Biometals. 2019 Jun.

Abstract

In recent years, iron sulfur (Fe-S) proteins have been identified as key players in mammalian metabolism, ranging from long-known roles in the respiratory complexes and the citric acid cycle, to more recently recognized roles in RNA and DNA metabolism. Fe-S cofactors have often been missed because of their intrinsic lability and oxygen sensitivity. More Fe-S proteins have now been identified owing to detection of their direct interactions with components of the Fe-S biogenesis machinery, and through use of informatics to detect a motif that binds the co-chaperone responsible for transferring nascent Fe-S clusters to domains of recipient proteins. Dissection of the molecular steps involved in Fe-S transfer to Fe-S proteins has revealed that direct and shielded transfer occurs through highly conserved pathways that operate in parallel in the mitochondrial matrix and in the cytosolic/nuclear compartments of eukaryotic cells. Because Fe-S clusters have the unusual ability to accept or donate single electrons in chemical reactions, their presence renders complex chemical reactions possible. In addition, Fe-S clusters may function as sensors that interconnect activity of metabolic pathways with cellular redox status. Presence in pathways that control growth and division may enable cells to regulate their growth according to sufficiency of energy stores represented by redox capacity, and oxidation of such proteins could diminish anabolic activities to give cells an opportunity to restore energy supplies. This review will discuss mechanisms of Fe-S biogenesis and delivery, and methods that will likely reveal important roles of Fe-S proteins in proteins not yet recognized as Fe-S proteins.

Keywords: ABCB7 and Atm1; CIAO1; HSC20; IRP1 and IRP2; Iron sulfur proteins; LYR motif.

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Figures

Fig. 1
Fig. 1
Two common types of Fe–S clusters, with sulfur represented by yellow spheres and iron represented by red spheres. Here, the cysteinyl sulfurs of proteins that ligate the clusters are shown on the outer margin of each cluster. (Color figure online)
Fig. 2
Fig. 2
IRP1 alternates between function as a cytosolic aconitase, which contains a [Fe4–S4] cluster in the active-site cleft, to an apoprotein form that lacks the cluster and binds to IRE stem-loop structures present in several iron transcripts. Upon binding, IRP1 represses translation of multiple transcripts that contain IREs near the 5′-end of the transcript, including Ferritin H and L transcripts, HIF2 α, erythrocytic ALAS, and the iron export protein, ferroportin. Conversely, IRP binding to mRNAs that contain IREs at the 3′-UTR protects transcripts from endonucleolytic degradation: the most well-known such transcript is transferrin receptor 1. Apo-IRP1 undergoes a large conformational change that creates a complex IRE-binding pocket, in which the bulge C of the IRE binds to a pocket in domain 4, and three residues of the loop make finger-like binding projections into regions of domain 3 that become accessible after conformational change. The length of the upper base-paired stem of the IRE derived from NMR structural solution (Addess et al. 1997) optimizes the distance between the main IRP contact points, the unpaired C of the stem, and residues A15, G16 and U17 of the loop, resulting in high affinity binding Figure from Rouault (2006)
Fig. 3
Fig. 3
A summary of pathways of cytosolic Fe–S biogenesis. The nascent cluster assembles on the ISCU scaffold using cytosolic isoforms of biogenesis proteins, and interaction with the chaperone/co-chaperone apparatus permits these clusters to transfer directly to NARFL and the NUBP1/NUBP2 complex. A subset of Fe–S proteins involved in DNA metabolism and ribosome biogenesis, including DNA repair, RNA metabolism, and numerous other cytosolic proteins obtain their Fe–S cluster cofactors after interacting with the CIA complex, depicted as composed of CIAO1, MMS19, and FAM96B. Figure modified from Kim et al. (2018)
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