Abstract
Iron–sulfur clusters are essential to almost every life form and utilized for their unique structural and redox-targeted activities within cells during many cellular pathways. Although there are three different Fe–S cluster assembly pathways in prokaryotes (the NIF, SUF and ISC pathways) and two in eukaryotes (CIA and ISC pathways), the iron–sulfur cluster (ISC) pathway serves as the central mechanism for providing 2Fe–2S clusters, directly and indirectly, throughout the entire cell in eukaryotes. Proteins central to the eukaryotic ISC cluster assembly complex include the cysteine desulfurase, a cysteine desulfurase accessory protein, the acyl carrier protein, the scaffold protein and frataxin (in humans, NFS1, ISD11, ACP, ISCU and FXN, respectively). Recent molecular details of this complex (labeled NIAUF from the first letter from each ISC protein outlined earlier), which exists as a dimeric pentamer, have provided real structural insight into how these partner proteins arrange themselves around the cysteine desulfurase, the core dimer of the (NIAUF)2 complex. In this review, we focus on both frataxin and the scaffold within the human, fly and yeast model systems to provide a better understanding of the biophysical characteristics of each protein alone and within the FXN/ISCU complex as it exists within the larger NIAUF construct. These details support a complex dynamic interaction between the FXN and ISCU proteins when both are part of the NIAUF complex and this provides additional insight into the coordinated mechanism of Fe–S cluster assembly.
Highlights
Iron–sulfur (Fe–S) clusters are inorganic cofactors that are essential for cell viability in almost every life form [1]
There are so many exciting labs providing new details related to how the iron–sulfur cluster (ISC) protein complex assembles and functions, and their molecular and atomic details provided by several structural biology groups, helps enrich our knowledge of the pathway
What is the role of the ISCU active site residues in coordinating metal loading and in assembling 2Fe–2S clusters? During assembly, is a single ISCU molecule loaded with one Fe(II) ion, requiring ISCU dimerization for 2Fe–2S cluster assembly, or is a full 2Fe–2S cluster assembled on each ISCU monomer when part of the NIAUF complex? Human D71 provides a ligand to the Zn(II) bound to ISCU in the NIAUF structure, a structure we conjecture more closely mimics a 2Fe–2S loaded scaffold and the site that matches that seen for the cluster loaded Methanothrix thermoacetophila scaffold [93]
Summary
Iron–sulfur (Fe–S) clusters are inorganic cofactors that are essential for cell viability in almost every life form [1]. While having multiple independent assembly pathways in prokaryotes provides these cells with the flexibility to assembly clusters under different environmental conditions, a complete reliance on the mitochondrial ISC pathway in eukaryotes to directly or indirectly assist in producing Fe–S clusters highlights the extreme importance of this pathway. It is, not surprising that several human diseases related to deficiencies in the ISC pathway’s normal activity (Friedreich’s ataxia (FRDA) and ISCU myopathy are just two diseases in this area) exist; the clinical importance for understanding ISC protein functions in these diseases is, obvious [11]. Cysteine desulfurase LYR MotNifF-cSo1ntainLYR Motif-containing protein 4 ing pIrSoDte1i1n 4
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