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School of Medicine Oregon Health & Science University CERTIFICATE School of Medicine Oregon Health & Science University CERTIFICATE OF APPROVAL This is to certify that the Ph.D dissertation of Gregory Kennard Scott Has been approved Mentor Committee Member Michael Forte Committee Member Regulation of PACS-1-directed protein trafficking By Gregory KennardcS_cott A Dissertation Presented to the Neuroscience Graduate Program and the Oregon Health & Science University School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2006 Table of Contents CHAPTER 1. INTRODUCTION ................................................................................. 1 Overview ................................ : .................................................................................... I The biosynthetic and endocytic pathways .................................................................... 4 Organelle identity ........................................................................................................ 7 Phospholipids .......................................................................................................... 8 The ARF and Rab GTPases ..................................................................................... 9 SNAREs ................................................................................................................. 13 Itinerant membrane proteins ...................................................................................... 14 Sorting motifs and adaptor proteins ........................................................................... 18 Tyrosine motifs, dileucine motifs and the adaptor proteins ..................................... 18 Acidic-dileucine motifs and the GGAs .................................................................... 21 Acidic cluster motifs and PACS-1 .......................................................................... 25 Tip47 and the Retromer complex ........................................................................... 29 Protein kinase CK2 .................................................................................................... 31 Conclusion ................................................................................................................ 33 CHAPTER 2 ................................................................................................................ 35 The phosphorylation state of an autoregulatory domain controls PACS-1- directed protein traffic Gregory K. Scott, Feng Gu, Colin M. Crump, Laurel Thomas, Lei Wan, Yang Xiang and Gary Thomas. Published in the EMBO Journal , December 1, 2003, 22(23):6234-6244 Introduction ............................................................................................................... 37 Results ...................................................................................................................... 41 Discussion ................................................................................................................. 49 Materials and Methods .............................................................................................. 55 Figure Legends .......................................................................................................... 63 CHAPTER 3 ................................................................................................................ 7 4 A PACS-1, GGA3 and CK2 complex regulates CI-MPR trafficking Gregory K. Scott, Hao Fei, Laurel Thomas, Guruprasad R. Medigeshi and Gary Thomas. Submitted for publication Introduction ............................................................................................................... 76 Results ...................................................................................................................... 77 Discussion ................................................................................................................. 90 Meterials and Methods .............................................................................................. 95 Figure Legends ........................................................................................................ 101 CHAPTER 4. DISCUSSION .................................................................................... 117 Summary ................................................................................................................. 117 Implications for P ACS-1 cargo binding .................................................................... 118 Implications for PACS-1 regulation ......................................................................... 119 Implications for CK2 binding and activation ............................................................ 121 Implications for GGA binding .................................................................................. 123 Implications for PACS-2 .......................................................................................... 125 Implications for neuronal function ........................................................................... 126 Conclusion ............................................................................................................... 127 APPENDIX A. VZV REVIEW ................................................................................. 148 Endocytosis of Varicella-Zoster Virus glycoproteins: virion envelopment and egress Charles Grose, Lucie Maresova, Guruprasad Medigeshi, Gregory K. Scott, and Gary Thomas. In Press with Horizon Press, Fa112006 Introduction ............................................................................................................. 150 1. Glycoprotein gE ................................................................................................... 151 2. VZV Glycoprotein gi ........................................................................................... 153 3. VZV Glycoprotein B ............................................................................................ 154 4. VZV Glycoprotein H ........................................................................................... 157 5.0. Incorporation of endocytosed VZV glycoproteins into virion envelopes ............ 159 6.0. Summary of trafficking pathways ...................................................................... 162 Figure Legends ........................................................................................................ 168 APPENDIX B. FURIN ACTIV ATION ..................................................................... l78 Identification of a pH sensor in the furin propeptide that regulates enzyme activation Sylvain F. Feliciangeli, Laurel Thomas, Gregory K. Scott, Ezhilkani Subbian, Chien Hui Hung, Sean S. Molloy, Franc;ois Jean, Ujwal Shinde and Gary Thomas In press in The Journal of Biological Chemistry Abstract ................................................................................................................... 179 Introduction ............................................................................................................. 180 Experimental Procedures ......................................................................................... 183 Results ..................................................................................................................... 188 Discussion ............................................................................................................... 196 Figure Legends ........................................................................................................ 202 APPENDIX C. PRELIMINARY RESULTS ............................................................ 212 11 Acknowledgments I am deeply indebted to my advisor, Dr. Gary Thomas, whose support, advice and scientific mentoring was essential for the development of this project and my training as a research scientist. I am also indebted to Laurel Thomas, who has contributed greatly to these studies, and has kept the lab running smoothly. Together, Gary and Laurel run a tight ship, and this dissertation reflects their hard work and determination to produce high quality research. The Thomas Lab is a team environment and the work presented in this dissertation could not have been done without the help of others. I was especially lucky to work with Feng Gu and Hao Fei, who each contributed greatly to these studies. I am also indebted to the members of the Thomas Lab, past and present who have been great advisors, collaborators and friends. Several individuals worked hard to keep my graduate training successful and interesting. Many thanks to: Neal Alto, Joe Asian, Rachel Dresbek, Chien­ Hui Hung, Stefanie Kaech-Petrie, Tom O'Hare and Oleg Varlamov. Finally, I extend special thanks to my parents, who have supported me through all levels of education, and to Laura Baraff, who has kept me sane through graduate school. lll Abstract The cation-independent mannose-6-phosphate receptor (CI-MPR) follows a highly regulated sorting itinerary to deliver hydrolases from the trans-Golgi network (TGN) to lysosomes. Cycling_ of CI-MPR between the TGN and early endosomes is mediated by GGA3, which directs TGN export, and PACS-1, which directs endosome-to­ TGN retrieval. Despite executing opposing sorting steps, GGA3 and PACS-1 both utilize a CK2-phosphorylated acidic cluster trafficking motif to bind the CI-MPR. But how CK2 coordinates these opposing roles is unknown. This thesis shows that an acidic cluster on PACS-1, which is highly
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