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Investigation of the Molecular Basis of Receptor Mediated Iron Release from Transferrin Shaina Byrne University of Vermont

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Investigation of the Molecular Basis of Receptor Mediated Iron Release from Transferrin Shaina Byrne University of Vermont University of Vermont ScholarWorks @ UVM Graduate College Dissertations and Theses Dissertations and Theses 2009 Investigation of the Molecular Basis of Receptor Mediated Iron Release from Transferrin Shaina Byrne University of Vermont Follow this and additional works at: https://scholarworks.uvm.edu/graddis Recommended Citation Byrne, Shaina, "Investigation of the Molecular Basis of Receptor Mediated Iron Release from Transferrin" (2009). Graduate College Dissertations and Theses. 38. https://scholarworks.uvm.edu/graddis/38 This Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks @ UVM. It has been accepted for inclusion in Graduate College Dissertations and Theses by an authorized administrator of ScholarWorks @ UVM. For more information, please contact [email protected]. INVESTIGATION OF THE MOLECULAR BASIS OF RECEPTOR MEDIATED IRON RELEASE FROM TRANSFERRIN A Dissertation Presented by Shaina Lynn Byrne to The Faculty of the Graduate College of The University of Vermont In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Specializing in Biochemistry May, 2009 Accepted by the Faculty of the Graduate College, The University of Vermont, in partial fulfiient of the requirements for the degree of Doctor of Philosophy, specializing in Biochemistry. Thesis Examination Committee: (L? AdGsor Anne B. Mason, Ph.D. Christopher L. Berger, P~.D.- [email protected], P~.V7-7 Deborah H. Darnon, Ph. D. Interim Dean, Graduate College Patricia A. Stokowski, Ph. D Date: March 20,2009 ABSTRACT Human serum transferrin (hTF) is a bilobal glycoprotein that plays a central role in iron metabolism. Each lobe of hTF (N- and C-lobe) can reversibly bind a single ferric iron. Iron binds to hTF at neutral pH in the plasma; diferric hTF binds to specific hTF receptors (TFR) on the cell surface and the complex undergoes receptor mediated endocytosis. The pH within the endosome is lowered to ~5.6 and iron is released from hTF. Apo hTF remains bound to the TFR and recycles back to the cell surface. Upon fusion with the plasma membrane, apo hTF dissociates from the TFR and is free to bind more iron and continue the cycle. The iron release process is complicated by various factors which include pH, anions, a chelator, lobe-lobe cooperativity and interaction with the TFR. All of these influence iron release in a complex manner. Because they are intricately linked, it is difficult to determine the effect of any single parameter. We have utilized stopped-flow and steady-state fluorescence and urea gel electrophoresis to dissect the iron release process as a function of lobe-lobe interactions, the presence of the TFR, and changes in pH and salt concentration. Application of recombinant protein production and site-directed mutagenesis has allowed us to generate a variety of hTF constructs in which the iron status of each lobe is completely controlled. Thus, we have created authentic monoferric hTFs unable to bind iron in one lobe, diferric hTFs with iron locked in one lobe and diferric hTF in which iron can be removed from both lobes. Importantly, we have produced the soluble portion of the TFR (sTFR) to analyze interactions between hTF and the sTFR and to monitor iron release from hTF/sTFR complexes. Together, we are able to provide a more precise picture of iron release from the two lobes of hTF in the presence and absence of the TFR. Steady-state fluorescence emission scans and urea gel electrophoresis provide a qualitative evaluation of the iron status of each construct after a predetermined incubation in iron removal buffer (i.e. an endpoint). However, these techniques do not provide information regarding the kinetic pathway to reach that endpoint. Combined with stopped-flow fluorescence time-based kinetics, a more precise assessment of the iron release process has been obtained. We have determined that changes in pH and salt affect endpoint iron release from the C-lobe, but not the N-lobe, however, the kinetics of iron release from both lobes are highly sensitive to pH and salt. Kinetic analysis in the absence and presence of the sTFR reveals the complexity of the iron release process. In the absence of the sTFR, the kinetics of iron release are insensitive to the iron status of the opposite lobe. However, in the presence of the sTFR, the kinetics of iron release from both lobes are affected by the iron status of the opposite lobe. Determination of conformational changes induced by anion binding, lobe-lobe communication and sTFR interactions have now been confidently assigned. We have created kinetic models of iron release from diferric hTF ± the sTFR and incorporated specific events pertaining to anion binding, lobe-lobe communication and conformational changes associated with sTFR interactions. We provide irrefutable evidence that a critical role of the sTFR is to accelerate the rate of iron release from the C-lobe, while decreasing the rate of iron release from the N-lobe such that the two lobes effectively release iron on a time scale relevant to one cycle of endocytosis. CITATIONS Material from this dissertation has been published in the following forms: Byrne, S. L., Leverence, R., Klein, J. S., Giannetti, A. M., Smith, V. C., MacGillivray, R.T.A, Kaltashov, I. A., and Mason, A. B.. (2006) Effect of glycosylation on the function of a soluble, recombinant form of the transferrin receptor, Biochemistry 45, 6663-6673. James, N. G., Byrne, S. L., and Mason, A. B.. (2008) Incorporation of 5- hydroxytryptophan into transferrin and its receptor allows assignment of the pH induced changes in intrinsic fluorescence when iron is released, Biochim. Biophys. Acta 1794, 532-540. Byrne, S. L., and Mason, A. B.. (2009) Human serum transferrin: A tale of two lobes. Urea gel and steady-state fluorescence analysis of recombinant transferrins as a function of pH, time and the sTFR, J. Biol. Inorg. Chem. In Press. ii DEDICATIONS This dissertation is dedicated to my family, especially my parents, Mike and Ruth, and my brother, Matt. Without your unwavering love and support this would not have been possible. Thank you for always standing by my side and encouraging me to pursue my dreams. I love you. iii ACKNOWLEDGEMENTS First and foremost, I would like to acknowledge and thank my mentor, Nan Mason, for giving me the opportunity to work in her laboratory and grow as both a scientist and a person; for allowing me to independently explore various aspects of this project while applauding my successes and helping me fix my failures; for encouraging me that “one day it will all come together”; I believe that day has arrived. I would also like to thank members of the Mason Lab, Nicholas James and Ashley Steere for their help, inspiring scientific conversation and friendship. I would like to thank my committee members, Drs. Stephen Everse, Christopher Berger, Robert Kelm and Deborah Damon for their guidance and advice. Furthermore, I thank my friends at UVM; for all the good times, stress relievers and support throughout this process, it wouldn’t have been possible without you. To my friends afar, thank you for all the visits over the years and for not losing touch, it means the world to me. To my extended family; Grampa, aunts, uncles and cousins, thank you for your curiosity, enthusiasm and support. I would also like to thank Dr. Kenneth G. Mann and the Thrombosis and Hemostasis Training Grant for financial support, Dr. Iwona Buskiewicz for taking time to train me on the stopped-flow spectrofluorimeter and the UVM Department of Biochemistry faculty, staff and fellow graduate students. Thank you. iv TABLE OF CONTENTS CITATIONS ....................................................................................................................... ii DEDICATIONS.................................................................................................................. ii ACKNOWLEDGEMENTS............................................................................................... iv LIST OF TABLES............................................................................................................. ix LIST OF FIGURES ............................................................................................................ x LIST OF ABBREVIATIONS USED ............................................................................... xii CHAPTER 1 COMPREHENSIVE LITERATURE REVIEW................................................................. 1 Iron and its Properties ..................................................................................................... 1 Iron Requirements and Dietary Absorption................................................................ 3 Iron Homeostasis ........................................................................................................ 4 Iron and Transferrin Associated Diseases....................................................................... 7 Iron Deficiency: Anemias........................................................................................... 7 Iron Overload: Hereditary Hemochromatosis............................................................. 7 Atransferrinemia ......................................................................................................... 9 The Transferrins............................................................................................................ 10 Serum Transferrin ....................................................................................................
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