Studies of Iron Sulfur Cluster Maturation and Transport
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2015
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu14296959672021-08-03T06:30:31Z Studies of Iron Sulfur Cluster Maturation and Transport Li, Jingwei Chemistry Cellular iron homeostasis is critically dependent on sensory and regulatory mechanisms that maintain a balance of intracellular iron concentrations. Divergence from a healthy iron concentration can result in common disease states such as anemia and ataxia. With the goal of understanding the molecular basis for such health problems, and advancing the knowledge based toward potential remedies, an understanding of the molecular details of cellular iron transport and the biological chemistry of iron species is an essential prerequisite. In that regard, iron-sulfur clusters are ubiquitous iron-containing centers in a variety of proteins and serve a multitude of roles that include electron transfer, catalysis of reactions, and sensors of cellular oxygen and iron levels.Recently, a substantial body of evidence has suggested an essential role for cellular glutathione (a molecule normally implicated with eliminating reactive oxygen species from cells) in the regulation, stabilization and biosynthesis of cellular iron-sulfur clusters in humans and other complex organisms. We have demonstrated that glutathione can naturally bind to iron-sulfur cluster precursors and have isolated and characterized this species and shown it to be stable under physiological conditions. More importantly, we have demonstrated that the glutathione-bound iron-sulfur cluster can be transported by a critical export protein from the cellular mitochondrion. The glutathione iron-sulfur cluster can also be bound by other critical cellular proteins and we hypothesize to be a new component of the so-called labile iron pool – an ill-defined collection of iron species prevalent inside a cell. To develop a further understanding of the cellular chemistry of these species, a multidisciplinary approach is being taken to elaborate their structural and functional chemistry. Proteoliposome studies are underway to explore the transport chemistry of the glutathione-iron-sulfur cluster complex as a viable substrate candidate for the mitochondrial export protein. Protein engineering of the transport protein will yield vital information on the interactions of the glutathione iron sulfur cluster with the protein and help to elucidate the mechanistic origin of the dysfunctional mitochondrial iron transport systems associated with this protein, which also underlie two common hereditary diseases (namely sideroblastic anemia and cerebellar ataxia). A variety of biophysical and molecular biology techniques, in addition to protein and lipid biochemistry are also being applied to the problem. For example, tiron chelation assay and flow cytometry assays are also applied to track and study the kinetic parameters of cluster transport across the membrane bilayer. My studies also extend to understanding the role of protein mobility in promoting the functional chemistry of these complex systems. We have found the dynamics of structural change to be unusual for many of the proteins involved in the cellular biosynthesis and transport of iron cofactors, and an understanding of these properties will help us to fully understand how they function in the broader context of the cell. 2015-05-19 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1429695967 http://rave.ohiolink.edu/etdc/view?acc_num=osu1429695967 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Chemistry |
| spellingShingle |
Chemistry Li, Jingwei Studies of Iron Sulfur Cluster Maturation and Transport |
| author |
Li, Jingwei |
| author_facet |
Li, Jingwei |
| author_sort |
Li, Jingwei |
| title |
Studies of Iron Sulfur Cluster Maturation and Transport |
| title_short |
Studies of Iron Sulfur Cluster Maturation and Transport |
| title_full |
Studies of Iron Sulfur Cluster Maturation and Transport |
| title_fullStr |
Studies of Iron Sulfur Cluster Maturation and Transport |
| title_full_unstemmed |
Studies of Iron Sulfur Cluster Maturation and Transport |
| title_sort |
studies of iron sulfur cluster maturation and transport |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2015 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1429695967 |
| work_keys_str_mv |
AT lijingwei studiesofironsulfurclustermaturationandtransport |
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1719438129540104192 |