Understanding the Role of Dre2 in Cellular Iron-Sulfur Cluster Trafficking
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Date
2018-05
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The Ohio State University
Abstract
Iron-sulfur (Fe-S) clusters are essential for cellular life. In eukaryotes, Fe-S clusters are biosynthesized in the mitochondria and then exported for further processing and uses in other parts of the cell. Transport of Fe-S clusters is an important but not fully understood process, and in yeast Dre2 is proposed as a part of the cytosolic assembly machinery that transports Fe-S clusters in the cytosol, however the pathway for Fe-S cluster reconstitution in cells is unclear. Dre2 has previously been shown to hold two clusters—a [4Fe-4S] cluster and a [2Fe-2S] cluster. Preliminary UV-Vis and circular dichroism (CD) data has shown Dre2 takes up Fe-S cluster through chemical reconstitution and release the Fe-S complex in glutathione extractions, supporting the notion it is involved in the transport of Fe-S clusters. Incubation of Dre2 with the Bola2-Grx3 heterodimer, an important protein complex for Fe-S cluster transport, and Nfu, a cytosolic Fe-S cluster protein, has shown successful Fe-S cluster transfer into Dre2. Incubations of apo Dre2 with holo Bola2-Grx3 at varying concentrations of wild-type and substituted derivatives of Dre2 were used to determine rates of transfer, the mechanism of Fe-S cluster binding, and the role of cysteine residues in Fe-S cluster binding. Additionally, Bola2-Grx3 complex has also been studied and chemical reconstitution of the holo homodimer Bola2 was confirmed by use of UV-Vis and CD. The combined data suggests Dre2, Nfu, and the Bola2-Grx3 complex are suggested to play an important role in cellular Fe-S cluster assembly, potentially linking mitochondrial and cytosolic assembly pathways. If this transport role is confirmed, Dre2 could be further studied for links to human disease. Because anamorsin, the human homolog of Dre2, has been implicated in neurodegenerative conditions, there may be a previously unidentified link between cluster transport and diseases such as Alzheimer's and Parkinson's.