The small inorganic Fe-S cluster (ISC) cofactor acts as an electron carrier in redox and catalytic reactions, and as a sulfur donor and environmental sensor. The ISC proteins can be found in mitochondria, cytoplasm and nucleus and are involved in energy production, tRNA modification and features of protein translation, DNA metabolism and repair. The steps in the assembly of iron-sulfur (Fe-S) clusters (ISC) and delivery to Fe-S proteins are part of the mitochondrial ISC biogenesis and the connec
ted cytosolic assembly (CIA) pathways; ISCs provide for the maturation of all Fe-S proteins. A subset of the mitochondrial ISC pathway, termed 'core' and the mitochondrial ISC transport are essential for the function of the CIA pathway. Details of the cytosolic pathway are described here.
A species still to be characterized, referred to as 'X-S', is delivered to the cytosol by the mitochondrial export pathway that includes the Abcb7 transporter, glutathione and the FAD-dependent intermembrane Gver (known as Alr) sulfhydryl oxidase. An initial [4Fe-4S] cluster is assembled on a scaffold composed of two P-loop NTPases, Nubp1 and 2, forming a heterotetramer. A loosely bound [4Fe-4S] is coordinated by a conserved motif at the C-terminus of Nubp1. A tightly bound [4Fe-4S] is coordinated by a ferredoxin-like motif at the N-terminus of Nubp1. As in the mitochondrial pathway, electrons need to be supplied and the CIA electron system is composed of Ndor1 diflavin protein and the Fe-S protein Ciapin1. The two proteins interact with each other. Based on EPR studies of the yeast counterpart, electrons from NADPH are transferred to the [2Fe-2S] of Ciapin1 via the FAD and FMN centers of Ndor1. Release of [4Fe-4S] from the Nubp complex is followed by its transfer and insertion into recipient proteins. It requires the presence of Narfl (known as IOP) for transfer and the CIA targeting complex composed of Ciao1 (known as Cia1), Fam96a and b (known as CIA2A and B, respectively) and Mms19 proteins for insertion. Particular combinations of targeting proteins deliver the cluster to specific cytosolic and nuclear recipient apoproteins. Fam96a (CIA2A), for instance, is dedicated to the insertion of [4Fe-4S] into the iron regulatory protein ACO1 (known as IRP1) and maturation of the aconitase holoprotein. The dual function ACO1 (IRP1), and IRP2, are involved in the post-transcriptional control of iron homeostasis. Many molecular aspects of the CIA pathway remain to be characterized.
