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Review
. 2020 May;45(5):411-426.
doi: 10.1016/j.tibs.2020.02.001. Epub 2020 Mar 6.

Outlining the Complex Pathway of Mammalian Fe-S Cluster Biogenesis

Nunziata Maio  1 , Tracey A Rouault  2
Affiliations
Review

Outlining the Complex Pathway of Mammalian Fe-S Cluster Biogenesis

Nunziata Maio et al. Trends Biochem Sci. 2020 May.

Abstract

Iron-sulfur (Fe-S) clusters (ISCs) are ubiquitous cofactors essential to numerous fundamental cellular processes. Assembly of ISCs and their insertion into apoproteins involves the function of complex cellular machineries that operate in parallel in the mitochondrial and cytosolic/nuclear compartments of mammalian cells. The spectrum of diseases caused by inherited defects in genes that encode the Fe-S assembly proteins has recently expanded to include multiple rare human diseases, which manifest distinctive combinations and severities of global and tissue-specific impairments. In this review, we provide an overview of our understanding of ISC biogenesis in mammalian cells, discuss recent work that has shed light on the molecular interactions that govern ISC assembly, and focus on human diseases caused by failures of the biogenesis pathway.

Keywords: CIAO1; FAM96B; HSC20; HSPA9; MMS19; frataxin; mitochondrial iron overload; multiple mitochondrial dysfunctions syndromes; secondary carriers.

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Figures

Figure 1.
Figure 1.. Iron-Sulfur Cluster (ISC) Biogenesis in Mammalian Mitochondria: An Overview of the Main Steps.
(Top left) Nascent ISCs are assembled de novo on the main scaffold protein ISCU. A cysteine desulfurase, NFS1, forms a dimer to which monomers of the primary scaffold ISCU bind at either end. ISD11 (also known as LYRM4) and acyl carrier protein (ACP) with its bound acyl chain are structural components of the core complex in eukaryotes. NFS1, aided by its cofactor pyridoxal phosphate (not shown), provides inorganic sulfur, removed from cysteine, to the nascent cluster. Transient binding of frataxin (FXN) in a pocket-like region between NFS1 and ISCU promotes sulfur transfer from NFS1 to ISCU. The cluster assembles upon ISCU when iron is provided together with the reducing equivalents needed to generate the final electronic configuration of the cluster. (Bottom left) A chaperone-cochaperone complex binds to the LPPVK motif of ISCU and either facilitates direct transfer of ISCs to recipient proteins (pathway A) or mediates transfer to secondary carriers (e.g., NFU1, GLRX5, ISCA1, ISCA2, and BOLA3; pathway B), which then donate ISCs to specific recipients (e.g., lipoic acid synthase and subunits of the respiratory chain complexes). (Right inset) Three different conformations of the mobile S-transfer catalytic loop of NFS1 during de novo ISC assembly upon ISCU in its trajectory from the catalytic conformation, in which Cys381 of NFS1 is close to pyridoxal-phosphate (PLP) and the substrate cysteine, to the intermediate conformation, recently structurally characterized [34] produced by FXN-binding, to the final ISC assembly conformation, in which the catalytic Cys381 of NFS1 donates sulfur to Cys138 of ISCU [32].
Figure 2.
Figure 2.. Comparison of the Three Recently Solved Crystal Structures of the Human Iron-Sulfur Cluster (ISC) Core Complex.
(A) Structure of the ISD11/acyl carrier protein (ACP) complex [Protein Data Bank (PDB) ID: 5USR]. The acyl chain (yellow) is covalently attached to the 4′-phosphopantotheine (4′-PP) group of ACP (orange) and fits within the three-helical structure of ISD11 (magenta). (B) Structure of the homodimeric (NFS1/ISD11/ACP/ISCU-Zn2+)2 complex [32] (PDB ID: 5WLW). NFS1 protomers (shades of blue), ISD11 (magenta), and ACP (orange) form a homohexameric core, with ISCU (green) bound at each end of the complex. (C) Structure of the homodimeric (NFS1/ISD11/ACP/ISCU-Zn2+-FXN)2 complex [34] (PDB ID: 6NZU). Frataxin (FXN) (tan) binds in a pocket-like region between ISCU and NFS1 protomers (colored as in B). (D) Structure of the (NFS1/ISD11/ACP)2 homodimeric complex in the ‘open’ conformation [33] (PDB ID: 5USR), in which the two NFS1 protomers make minimal contacts with each other, and ISD11 mediates the interactions between the NFS1 subunits.
Figure 3.
Figure 3.. Alternative Proposed Models of Cytoplasmic Iron-Sulfur Cluster (ISC) Biogenesis.
(A) Assembly of cytoplasmic ISCs begins in mitochondria with components of the early ISC machinery synthesizing a sulfur-containing precursor (X-S) that is subsequently exported to the cytosol by the ABC transporter Atm1 (ABCB7 in humans) and utilized by the cytoplasmic ISC assembly machinery for the biosynthesis of [4Fe-4S] clusters upon the main heterotetrameric complex, comprising NUBP1 and NUBP2 [67]. (B) Alternative isoforms of the core early ISC factors are present in the cytosol of mammalian cells, where they initiate de novo assembly of [2Fe-2S] clusters on the main cytosolic scaffold protein ISCU1. A dedicated chaperone/cochaperone system, comprising HSPA9 and HSC20, either facilitates direct ISC transfer to a subset of recipient cytosolic proteins (e.g., CIAPIN1, NUBP1, and NUBP2) or mediates the transfer of ISCs to enzymes involved in DNA metabolism through direct binding of HSC20 to the LYR motif of the CIAO1 component of the cytosolic ISC assembly (CIA)-targeting complex [78].
Figure I.
Figure I.. Examples of Iron-Sulfur Clusters (ISCs) Found in Proteins.
(A) The common rhombic [2Fe-2S] clusters are initially assembled from inorganic iron and sulfur upon the main scaffold protein ISCU and they can be utilized to generate more complex Fe-S cofactors. (B) The tetranuclear or cubane clusters are formed by reductive coupling of two [2Fe-2S] clusters, in a process that requires two electrons (2e−). [4Fe-4S] clusters have the capability to delocalize electrons between iron sites (as depicted by the tan cloud-like frames, which illustrate that the iron-associated electrons are highly delocalized between neighboring iron atoms). (C) The configurations of Fe-S cofactors can be more complex in the P-cluster of nitrogenase or in the iron-molybdenum cofactor of nitrogenase depicted in (D), where an interstitial carbon atom occupies the core of the cofactor.
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