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ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Yu Fukuda University of Tennessee Health Science Center

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University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 12-2008 ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Yu Fukuda University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Chemicals and Drugs Commons, and the Medical Sciences Commons Recommended Citation Fukuda, Yu , "ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters" (2008). Theses and Dissertations (ETD). Paper 345. http://dx.doi.org/10.21007/etd.cghs.2008.0100. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. ABCB6 Is a Porphyrin Transporter with a Novel Trafficking Signal That Is Conserved in Other ABC Transporters Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Interdisciplinary Program Research Advisor John D. Schuetz, Ph.D. Committee Linda Hendershot, Ph.D. James I. Morgan, Ph.D. Anjaparavanda P. Naren, Ph.D. Jie Zheng, Ph.D. DOI 10.21007/etd.cghs.2008.0100 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/345 ABCB6 IS A PORPHYRIN TRANSPORTER WITH A NOVEL TRAFFICKING SIGNAL THAT IS CONSERVED IN OTHER ABC TRANSPORTERS A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Yu Fukuda December 2008 Portions of Chapter 2 2006 by Nature Publishing Group All other material 2008 by Yu Fukuda All rights reserved ii DEDICATION I would like to dedicate this dissertation to my parents, Toshio and Etsuko Fukuda for nurturing me with constant love and support so that my roots are firmly grounded to withstand any weather. iii ACKNOWLEDGMENTS I would like to acknowledge and thank everyone who contributed to my dissertation work in the past years. First and foremost I would like to thank my research advisor, Dr. John Schuetz, for his willingness to take me as his first graduate student, his patience, his guidance and his trust. He taught me to stay focused on important issues and encouraged me to develop as a scientist. I would like to also thank all the past and present members of the Schuetz lab for their help, friendship and support. A special thanks to Dr. Partha Krishnamurthy for all the advice he has given me and for all the discussions we had together. I would like to also thank Jessie Morgan for her continuous support and for teaching me the ‘Southern’ styles. I would like to thank Dr. Daxi Sun for helping me with plasmid construction initially, Yao Wang for FACS analysis and Dr. Guoqing Du for plasmids. I also like to thank Bath student, Dan Martin, for repeating the pull-down assays. I would also like to extend my gratitude to Dr. Erin Schuetz for her helpful and insightful comments during the lab meetings. I would also like to thank my graduate committee, Dr. Linda Hendershot, Dr. Jim Morgan, Dr. A. P. Naren and Dr. Jie Zheng for taking part in my graduate training, their guidance and their commitment. I would also like to thank Dr. Jufang Shan for homology modeling help, Yi Jin for showing me how to do pulse chase studies, and Dr. Joseph Bryan at Pacific Northwest Diabetes Research Institute for his contribution to the SUR1 experiment. I would also like to thank Flow cytometry lab for running PPIX measurements. A special thanks to fellow graduate students especially my classmates for their support and for their friendship. I would like to thank Dr. Louise Treanor for her friendship. I would like to thank my best friend Patrick Siglin for his continuous support and for motivating me to be the best person I can be. I would also like to express my sincere thanks to Dr. Yasuyuki Igarashi, Dr. Akio Kihara and Dr. Gabor Tigyi for their support and for encouraging me to pursue my doctorate degree in the United States. Last, but certainly not least, I would like to thank my family and friends. Without their support, none of this would have been possible. iv ABSTRACT The ATP-binding cassette (ABC) transporters play an important role as a barrier to protect cells from the accumulation of toxic xenobiotics and metabolites due to their ability to translocate a wide array of compounds across lipid bilayers. However, many ABC transporters, especially the ones localized in the intracellular organelles, are involved in critical biological processes such as antigen presentation. The core unit of ABC transporters contains two functional domains: the membrane spanning domain (MSD) and the nucleotide binding domain. The full transporters contain two of these units in tandem in a single polypeptide, whereas the half transporters only contain one and must homo- or hetero-dimerize in order to exert their functions. A half transporter ABCB6 has been shown to localize in mitochondria and suggested to play a role in iron homeostasis; however, its function remained elusive. Therefore, we aimed to characterize several aspects of ABCB6: identification of substrates, physiological role, transport mechanism and intracellular trafficking. In this study, we show that ABCB6 is a homodimeric mitochondrial outer membrane protein. Furthermore, we identified ABCB6 as a porphyrin transporter that facilitates heme biosynthesis, in which the intermediates must be shuttled between mitochondria and the cytosol. Translocation of substrates by ABC transporters occurs in an ATP-dependent manner, although the role of ATP binding and hydrolysis in the transport process remains controversial. Taking advantage of its ability to bind hemin conjugated to agarose beads, we demonstrate that the ATP binding at the NBD is sufficient to induce a conformational change to a low affinity state in ABCB6. In an attempt to understand how ABCB6 trafficks intracellularly, we identified a post-translational modification that indicates ER to Golgi trafficking during its maturation. Moreover, we identified a novel N-terminal disulfide bond that plays an important role in the ER exit of ABCB6. This disulfide bond motif is found in other ABC family members and the loss of the conserved cysteine residue in ABCC8/SUR1 is the genetic basis for hyperinsulinemic hypoglycemia. Because ER redox status appears to play an important role in the trafficking of these proteins, expression patterns of ABC transporters may be altered in pathophysiological conditions such as diabetes where microsomal redox status is shifted. v TABLE OF CONTENTS CHAPTER 1. INTRODUCTION................................................................................... 1 1.1. Historic Overview: Discovery of P-glycoprotein and ABC Protein Superfamily.... 1 1.2. ABC Transporters................................................................................................. 3 1.2.1. ABC Transporters and MDR Phenotypes ................................................. 7 1.2.2. Physiological Roles of ABC Transporters ................................................ 8 1.2.3. ABC Transporters and Diseases/Phenotypes ...........................................11 1.2.4. Architecture of ABC Transporters...........................................................11 1.2.5. Transport Mechanism..............................................................................14 1.2.6. Regulation of ABC Transporters.............................................................16 1.3. Half Transporters in ABCB Subfamily.................................................................17 1.3.1. ABCB7/Atm1p .......................................................................................18 1.3.2. ABCB10/ABC-me ..................................................................................20 1.3.3. Identification of ABCB6 (PRP/UMAT/MTABC3)..................................20 1.3.4. Transcriptional Regulation of ABCB6.....................................................21 1.4. Heme Biosynthesis...............................................................................................21 1.4.1. Heme Biosynthesis and Diseases.............................................................22 1.4.2. Compounds That Interfere with Heme Biosynthesis................................24 1.4.3. Photodynamic Therapy ...........................................................................25 1.5. Heme and Porphyrin Transporters........................................................................25 1.5.1. Heme Importer: Heme Carrier Protein 1..................................................26 1.5.2. Heme/Porphyrin Exporters......................................................................26 1.5.3. Intracellular Porphyrin Transporters........................................................27 CHAPTER 2. CHARACTERIZATION OF ABCB6 AS A PORPHYRIN TRANSPORTER....................................................................................29 2.1. Introduction .........................................................................................................29 2.2. Experimental Procedures......................................................................................31 2.2.1. Cell Culture and Transfection..................................................................31
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