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Glutathione Coordinated Iron-Sulfur Cluster Transport via a Mitochondrial ABC Transporter

Pearson, Stephen A

Abstract Details

2019, Doctor of Philosophy, Ohio State University, Biophysics.
Iron-sulfur cluster proteins play key roles in a multitude of physiological processes; including gene expression, nitrogen and oxygen sensing, electron transfer, and DNA repair. To function, such proteins require delivery of an Fe-S cluster to the apo form. Initial formation of such clusters arises in the mitochondria on iron-sulfur cluster scaffold proteins, which are then transferred to apo targets within the mitochondria. Iron-sulfur clusters are also required in proteins in the cytosol and nucleus for proper protein function. No de novo Fe-S cluster biosynthesis machinery is known to exist in the cytosol; therefore it is believed that the clusters need to be transported out of the mitochondria. Just like Fe-S clusters, ABC transporters are found in all living organisms, 48 of which have been identified in humans. These ABC transporters function as both importers and exporters and are found in cellular and intracellular membranes. ABC transporters are of great interest to the scientific community, as up to 50% of all drugs target such proteins. Additionally, diseases such as cystic fibrosis, adrenoleukodystrophy, Stargardt disease, and sideroblastic anemia are caused by mutations in ABC transporters, while multi-drug resistance results from overexpression of certain ABC exporters. All ABC transporters work by the same general mechanism, requiring binding and hydrolysis of ATP to promote conformational changes that allow for substrate movement. While being found in all known living organisms, the iron-sulfur cluster biosynthesis machinery is highly conserved from bacteria to man, suggesting that mitochondria in eukaryotes would have inherited the ability to synthesis iron-sulfur clusters from simple bacteria, eventually becoming mitochondria as described in the endosymbiotic theory. Interestingly, the bacterial proteins that are most similar to human ABCB7 are found in alphaproteobacteria, the class that contains the prokaryote that was thought to evolve into mitochondria. A bacterial homologue, NaAtm1p, has been shown to likely be a heavy metal exporter, exporting metals coordinated to glutathione. This binding site was likely conserved in its eukaryotic homologues, allowing for transport of glutathione coordinated molecules. Recently published data on the yeast homologue has shown that the mitochondrial inner membrane protein Atm1p has the ability to transport glutathione-coordinated iron-sulfur clusters, which may connect the mitochondrial and cytosolic iron-sulfur cluster assembly systems. Four of the five distinct disease-causing missense mutations of the human homologue (ABCB7) result in X-linked sideroblastic anemia, with one of those residues, E433K, positioned in the proposed substrate binding pocket. This work builds upon previous studies conducted with Saccharomyces cerevisiae Atm1p, further investigating the mechanism of cluster transport and creating a series of mutations to evaluate the influence of mutations in ABCB7 that result in disease states. Additionally, WT and E433 derivatives of human ABCB7 were compared to the yeast homologue.
James Cowan, . (Advisor)
Ross Dalbey (Committee Member)
Richard Swenson (Committee Member)
Hannah Shafaat (Committee Member)
301 p.

Recommended Citations

Citations

  • Pearson, S. A. (2019). Glutathione Coordinated Iron-Sulfur Cluster Transport via a Mitochondrial ABC Transporter [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1563172940234769

    APA Style (7th edition)

  • Pearson, Stephen. Glutathione Coordinated Iron-Sulfur Cluster Transport via a Mitochondrial ABC Transporter. 2019. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1563172940234769.

    MLA Style (8th edition)

  • Pearson, Stephen. "Glutathione Coordinated Iron-Sulfur Cluster Transport via a Mitochondrial ABC Transporter." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1563172940234769

    Chicago Manual of Style (17th edition)