Iron-Sulfur (Fe-S) clusters are essential for life, as they are widely utilized in nearly every biochemical pathway. When bound to proteins, Fe-S clusters assist in catalysis, signal recognition, and energy transfer events, as well as additional cellular pathways including cellular respiration and DNA repair and replication. In Eukaryotes, Fe-S clusters are produced through coordinated activity by mitochondrial Iron-Sulfur Cluster (ISC) assembly pathway proteins through direct assembly, or through the production of the activated sulfur substrate used by the Cytosolic Iron-Sulfur Cluster Assembly (CIA) pathway. In the mitochondria, Fe-S cluster assembly is accomplished through the coordinated activity of the ISC pathway protein complex composed of a cysteine desulfurase, a scaffold protein, the accessory ISD11 protein, the acyl carrier protein, frataxin, and a ferredoxin; downstream events that accomplish Fe-S cluster transfer and delivery are driven by additional chaperone/delivery proteins that interact with the ISC assembly complex. Deficiency in human production or activity of Fe-S cluster containing proteins is often detrimental to cell and organism viability. Here the authors summarize what is known about the structure and functional activities of the proteins involved in the early steps of assembling [2Fe-2S] clusters before they are transferred to proteins devoted to their delivery. The goal is to provide a comprehensive overview of how the ISC assembly apparatus proteins interact to make the Fe-S cluster which can be delivered to proteins downstream to the assembly event.

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