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LRP1 Endocytosis Is Regulated by KIF13B Through the Interaction with Hdlg1

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LRP1 Endocytosis Is Regulated by KIF13B Through the Interaction with Hdlg1 LRP1 endocytosis is regulated by KIF13B through the interaction with hDLG1 A thesis submitted by Joslyn E. Mills in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Cellular and Molecular Physiology Tufts University Sackler School of Graduate Biomedical Sciences May 2018 Advisors: Laura Liscum, PhD and Athar Chishti, PhD Abstract KIF13B, a kinesin-3 family motor, was originally identified by virtue of its biochemical interaction with human homolog of Drosophila discs large tumor suppressor (hDLG1). Unlike its homolog KIF13A, the KIF13B contains a carboxyl-terminal CAP-Gly domain. To investigate the specific functional role of the CAP-Gly domain in KIF13B, and its possible compensation by KIF13A, we developed two mouse models. One mouse model expresses a truncated form of KIF13B protein lacking only its CAP-Gly domain (KIF13BΔCG), whereas the second model lacks the full-length KIF13A (KIF13A FLKO). Using these mouse models, we show that the KIF13BΔCG mice exhibit relatively higher levels of serum cholesterol consistent with the reduced uptake of [3H]CO-LDL in KIF13BΔCG mouse embryo fibroblasts. In contrast, the serum level of factor VIII was not significantly elevated in the KIF13BΔCG as compared to wild-type mice, suggesting that the CAP-Gly domain of KIF13B selectively regulates Low density lipoprotein Related Protein 1-mediated lipoprotein endocytosis. No elevation of either serum cholesterol or factor VIII was observed in the KIF13A FLKO. Moreover, we found that the deletion of the CAP-Gly domain caused subcellular mislocalization of truncated KIF13B with concomitant mislocalization of LRP1. To further delineate the biochemical basis of the LRP1-KIF13B complex at the plasma membrane, we discovered that the cytoplasmic domain of LRP1 interacts specifically with the alternatively spliced I3 domain of hDLG1, which in turn recognizes the MBS domain of KIF13B. Together, this study provides evidence for the biochemical basis of LRP1-hDlg1-KIF13B complex formation, which regulates LRP1-mediated interactions with implications in metabolism, cell polarity, and development. ii Dedication To my family, making you proud was a driving force for my hard work and dedication to the scientific field. To my friends, with whose little help I get by. And especially to Dennis, who deserves his own degree for the support he has given me while I pursue mine, and beyond. iii Acknowledgements First, I want to thank my co-mentors, Dr. Laura Liscum and Dr. Athar Chishti for their immeasurable support and confidence in me. Laura has supported me from the beginning through all the ups and downs, and we finally made it to the end! In addition to supporting my research, there is no one better than her to prepare me for a career in teaching. Athar was my champion for taking me into his lab late in the game. Without him, I would not have a body of work that is so worthy of defending. Next, I want to thank my committee members, Dr. Brent Cochran and Dr. Peter Juo, for their insightful advice and guidance; Brent, for his patience in helping me through all my different projects, and Peter, for taking over as my chair for this final project. I also want to thank Dr. Jerry Faust, my original committee chair. In addition to the important scientific conversations we had, I am grateful for him knowing when I needed to chat about something else to forget about my frustration with my projects for a while. I want to thank Dr. Toshi Hanada for laying the groundwork for this project and sharing it with me, and I only hope I have done it justice. Additionally, I want to thank the support staff, Andrea Flaherty, Elaine Ross, Jeanne Rose, Karen Hatch, and Di Pierce, for making it feel like you are all my own personal support group. Your friendships mean the world to me, and I am so grateful I had you all to get though the tough times as well as the happy times. Finally, thank you to all that contributed to the manuscript and foundation of this project: Yunzhe Lu, Yoichi Hase, Janis Lem, Lauren Richie, Bina Julian, Madhumouli Chatterjee from Dr. Gary Gilbert’s lab, Dr. Joachim Herz and Rebekah Hewitt, Dr. Alice Lichtenstein and HNRC Nutrition Evaluation Lab: Gayle Petty and Stephanie Thea Leon Valliere, TUSM histology core: Nathan Li, Tufts University Core Facility, and Dr. Roderick Bronson from HSM. iv Table of Contents Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iii Acknowledgements ............................................................................................................ iv Table of Contents ................................................................................................................ v List of Figures ................................................................................................................... vii List of Copyrighted Materials .......................................................................................... viii List of Abbreviations ......................................................................................................... ix Chapter 1: INTRODUCTION............................................................................................. 1 1.1 Kinesin motor proteins .............................................................................................. 1 1.1.1 KIF13 Family ..................................................................................................... 1 1.1.2. KIF13B and endocytosis ................................................................................... 6 1.2 hDLG1 background ................................................................................................... 7 1.3 LRP1 background .................................................................................................... 10 Chapter 2: MATERIALS AND METHODS .................................................................... 14 2.1. Materials ................................................................................................................. 14 2.2. Mouse studies ......................................................................................................... 15 2.2.1. Generation of mouse models ........................................................................... 15 2.2.2. Measurement of serum lipids in mice.............................................................. 15 2.2.3. Measurement of plasma factor VIII in mice .................................................... 16 2.2.4. Liver histology and immunohistochemistry .................................................... 17 2.2.5. Fibroblasts establishment ................................................................................ 17 2.3. Cell culture ............................................................................................................. 18 2.3.1. LRP1 immunofluorescence ............................................................................. 18 2.3.2. LRP1 Western blotting .................................................................................... 18 2.3.3. LPDS, LDL, [3H]-LDL, and [3H]-Cholesteryl oleate production ................... 19 2.3.4. [3H]-LDL uptake and hydrolysis assay ........................................................... 19 2.3.5. Cholesterol esterification assay ....................................................................... 20 2.3.6. Surface protein biotinylation ........................................................................... 20 2.4. Cloning and protein interaction assays................................................................... 21 2.4.1. Cloning and site directed mutagenesis ............................................................ 21 2.4.2. Pull-down assays ............................................................................................. 22 2.4.3. Co-Immunoprecipitation ................................................................................. 23 v 2.5. Statistical analysis .................................................................................................. 23 Chapter 3: RESULTS ....................................................................................................... 24 3.1. Mouse Characterization.......................................................................................... 24 3.1.1. Generation of KIF13A and KIF13B mouse models ........................................ 24 3.1.2. Effect of CAP-Gly domain deletion in mice on cholesterol and factor VIII phenotype................................................................................................................... 27 3.1.3. Liver histology ................................................................................................. 30 3.1.4. Effect of CAP-Gly domain deletion on KIF13B protein localization ............. 32 3.2 Cell culture studies .................................................................................................. 34 3.2.1. LRP1 status in fibroblasts lacking KIF13B CAP-Gly domain ........................ 34 3.2.2. Biotinylation of surface LRP1 ......................................................................... 36 3.3 Cloning, expression, and protein interaction assays ............................................... 36 3.3.1. TRX-LRP1 cloning and purification ..............................................................
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