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Studies of Iron Sulfur Cluster Maturation and Transport DISSERTATION Presented in Partial Fulfillment of the Requirements for Th Studies of Iron Sulfur Cluster Maturation and Transport DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jingwei Li Graduate Program in Chemistry The Ohio State University 2015 Dissertation Committee: Professor James A. Cowan, Advisor Professor Ross E. Dalbey Professor Claudia Turro Copyright by Jingwei Li 2015 Abstract 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 ii 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 iii 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. iv Dedication This document is dedicated to my parents. v Acknowledgments My graduate school experiences have taught me many lessons, and also helped me to grow as a scientist and as a person. I am heartily grateful to my adviser, Professor James A. Cowan, for his encouragement and guidance during this time. The great support and inspiring research environment Dr. Cowan has provided made it possible for me to explore a vast field of scholarly ideas and experiments. Dr. Cowan’s valuable advices have also helped to shape my career goal as a physician scientist, and his encouragements and supports provided a solid foundation for my pursuit of a career in biomedical research. I am also thankful to my committee members: Dr. Ross Dalbey and Dr. Claudia Turro, for the valuable insights they shared with me, and the encouragement they have provided. It has been an honor and a pleasure for me to work with so many great colleagues. I would like to thank Wenbin, Jeff, Seth and Lalintip for the great help they gave me when I joined the group. I have learned especially a great deal in biochemical theories and techniques from Wenbin, and his help and support have been an essential element to my achievements during graduate school. I have enjoyed great discussions with my vi colleagues: James, Jessica, Insiya, Zhen, Steve, Christine, Andrew and Sam, and deeply appreciate their valuable comments and suggestions on my projects and manuscripts. I would like to thank Steve for his tireless efforts in collaborating with me on various projects we worked on during the last stage of my graduate school career. I would like to thank Dr. Dennis Bong for his generosity by letting me using his instruments such as the Dynamic Light Scattering spectrometer and the ultracentrifuge for my proteoliposome studies. I would like to thank Drs. Chunhua Yuan and Tanya Young for their valuable insights and enormous help in NMR experiments. I’d like to thank Drs. Cecilia Chain, Gustavo Pasquevich and Alberto Pasquevich for their collaborative effort in Mossbauer studies. Most importantly, I am thankful to my mother and all of her encouragement, love and support during my academic career. My accomplishments and achievements would not have been possible without her help. vii Vita 2009....................................... B.S. Chemistry, The Ohio State University 2009 to present ...................... Graduate Teaching and Research Associate, Department of Chemistry, The Ohio State University Publications 1. Jingwei Li and J.A. Cowan, “Glutathione-Coordinated [2Fe-2S] Cluster. A Viable Physiological substrate for Mitochondrial ABCB7 Transport”, Chemical Communications, 10.1039/C4CC09175B 2. Wenbin Qi, Jingwei Li and J.A. Cowan, “A structural model for glutathione- complexed iron–sulfur cluster as a substrate for ABCB7-type transporters” Chemical Communications, 2014, 50, 3795-3798 3. Jingwei Li, Shu Ding and J.A. Cowan, “Iron-Sulfur Cluster Biosynthesis: Thermodynamic and Structural analysis of Human NFU Conformational Chemistry” Biochemistry, 2013, 52, 4904-4913 4. Wenbin Qi, Jingwei Li, C. Y Chain, G.A. Pasquevich, A. F. Pasquevich, and J. A. Cowan “Glutathione-Complexed Iron-Sulfur Clusters. Reaction Intermediates and viii Evidence for a Template Effect Promoting Assembly and Stability”, Chemical Communications, 2013, 49, 6313-6315. 5. Wenbin Qi, Jingwei Li and J.A. Cowan, “Human Ferredoxin-2 displays a unique conformational change” Dalton Transactions. 2013, 42, 3088-3091. 6 Wenbin Qi, Jingwei Li, C. Y Chain, G.A. Pasquevich, A. F. Pasquevich, and J. A. Cowan Glutathione Complexed Fe-S Centers. J. Am. Chem. Soc. 2012 134, 10745-10748. Fields of Study Major Field: Chemistry ix Table of Contents Abstract ............................................................................................................................... ii Dedication ........................................................................................................................... v Acknowledgments.............................................................................................................. vi Vita ................................................................................................................................... viii Publications ...................................................................................................................... viii Table of Contents ................................................................................................................ x List of Tables .................................................................................................................. xvii List of Figures ................................................................................................................... xx List of Schemes ............................................................................................................. xxvii Chapter 1: Introductions – Iron and iron-sulfur clusters: their homeostasis and biological relevance. ............................................................................................................................ 1 Background ..................................................................................................................... 1 Mechanism of iron sulfur cluster formation .................................................................. 12 Maturation of iron-sulfur cluster containing proteins ................................................... 15 Redox properties of iron-sulfur cluster proteins ........................................................... 17 x Mitochondrial export of iron-sulfur clusters ................................................................. 19 Study of cluster transport using proteoliposome models .............................................. 23 References ..................................................................................................................... 25 Chapter
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