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A Phosphoinositide Conversion Mechanism for Exit from Endosomes

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A Phosphoinositide Conversion Mechanism for Exit from Endosomes A phosphoinositide conversion mechanism for exit from endosomes Inaugural-Dissertation to obtain the academic degree Doctor rerum naturalium (Dr. rer. nat.) submitted to the Department of Biology, Chemistry and Pharmacy of Freie Universität Berlin by KATHARINA KETEL from Berlin, Germany 2016 2 Period of doctorate study: January 2011 until February 2016 Supervisor: Prof. Dr. Volker Haucke Institute: January 2011 until August 2012: Institute of Chemistry and Biochemistry, Freie Universität Berlin September 2012 until February 2016: Leibniz Institute for Molecular Pharmacology (FMP), Berlin 1st Reviewer: Prof. Dr. Volker Haucke 2nd Reviewer: Prof. Dr. Christian Freund Date of defense: June 6th 2016 3 Acknowledgements I am deeply grateful for the excellent training and guidance I received from my supervisor Prof. Volker Haucke during the time of my PhD thesis as well as throughout my undergraduate studies. Your willingness to extensively and very frequently discuss every little detail of my project, your ability to guide me through difficult parts of the project and your enthusiasm for science were a constant source of motivation and essential for the success of my project. I owe special thanks to Marnix Wieffer and Michael Krauß, who spent a lot of time helping me to get started in the lab, to overcome numerous experimental problem, I was not sure how to deal with, and frequently joined in discussions about my project with excellent advice. I am really grateful for your experimental support, Michael, and the time you invested in the project during our paper revision. Further, I would like to thank Jocelyn Laporte and his group, especially Anne-Sophie Nicot, at the IGBMC in Strasbourg for their support and a very fruitful collaboration, and Carsten Schultz and his group at the EMBL in Heidelberg for their support and constant supply with PIP/AMs. I owe special thanks to Dmytro Puchkov for the ultrastructural analysis and Eberhard Krause for mass spectrometry done within this project. I also need to acknowledge Markus Wenk and Federico Torta at the Singapore Lipidomics Incubator for joining the project at a very late stage, when we urgently needed help from lipidomics specialists. It was a pity that experiments did not work out as planned. I would further like to express my gratitude to two very skilled technicians in the AG Haucke lab: Silke Zillmann and Delia Löwe. Without your help it would have been impossible to achieve so much within the limited amount of time I had during the paper revision. Further, I would like to acknowledge all past and present members of the AG Haucke lab, including the AG Schmoranzer, AG Maritzen and AG Krauß. Without you work would have been less cheerful, enjoyable and efficient: Jelena Bacetic, Marietta Browarski, Caraoline Bruns, Katrin Diesenberg, Marielle Eichborn-Grüning, Fabian Feutlinske, Uwe Fink, Niclas Gimber, Gala Claßen, Claudia Gras, Isabelle Grass, Kira Gromova, Sabine Hahn, Burkhard Jakob, Lisa Jerndal, Maria Jäpel, Natalie Kaempf, Christina Kath, Peter Koch, 4 Gaga Kochlamazashvili, Natalia Kononenko, Seong Joo Koo, Ludwig Krabben, Marijn Kuijpers, André Lampe, Wen-Ting Lo, Martin Lehmann, Gregor Lichtner, Tania López Hernández, Marta Maglione, Andrea Marat, Tanja Maritzen, Julia Mössinger, Maria Mühlbauer, Arndt Pechstein, Jasmin Podufall, York Posor, Yijian Rao, Christine Rückert, Linda Sawade, Hannah Schachtner, Claudia Schmidt, Jan Schmoranzer, Irene Schütz, Kyungyeun Song, Wiebke Stahlschmidt, Tolga Soykan, Susanne Thomsen, Anela Vukoja, Alexander Wallroth, Ingeborg Walther, Susanne Wojtke, Haibin Wang, Anna Wawrzyniak and Mirjana Weimershaus. Most importantly, I would like to express my gratitude to my parents, my husband and my brother who supported me throughout my thesis, no matter how time consuming, and made everyday life beside work doable. The knowledge that I have your support no matter what I decide to do is most reassuring. I Table of Content I Table of Content................................................................................................................. 5 II Zusammenfassung.............................................................................................................. 8 III Summary ...................................................................................................................... 10 1 Introduction ...................................................................................................................... 11 1.1 Defective PI homeostasis and membrane remodeling might cause X-linked centronuclear myopathy ....................................................................................................... 11 1.1.1 Exocytic membrane transport is counterbalanced by retrograde traffic......... 11 1.1.2 Phosphoinositides determine membrane identity............................................. 12 1.2 Membrane traffic is regulated by phosphoinositides ............................................... 15 1.2.1 Phosphoinositides serve as spatio-temporal landmarks .................................. 15 1.2.2 PI(4,5)P2-to-PI(3)P conversion in endocytic membrane traffic ...................... 16 1.2.3 Endosomal sorting occurs via tubular cargo-enriched subdomains ............... 17 1.2.4 Exocyst tethering in endosomal exocytosis is regulated by endosomal and cell surface determinants ........................................................................................................ 20 1.3 Myotubularins are a family of PI 3-phosphatases.................................................... 22 1.3.1 MTM1 regulates endosomal PI(3)P turnover and membrane dynamics ........ 23 1.3.2 Other myotubularin family members contribute to endosomal PI(3)P turnover ………………………………………………………………………………...24 1.4 Endosomal PI(4)P is synthesized by type II PI 4-kinases........................................ 26 1.5 Aims of this study .................................................................................................... 27 2 Material and methods....................................................................................................... 28 2.1 Materials................................................................................................................... 28 2.1.1 Chemicals......................................................................................................... 28 2.1.2 Buffers, Media and Solutions ........................................................................... 28 2.1.3 DNA Oligonucleotides...................................................................................... 31 2.1.4 Small interference RNA Oligos ........................................................................ 31 2.1.5 Plasmid vectors ................................................................................................ 32 2.1.6 Molecular weight standards............................................................................. 34 2.1.7 Antibodies......................................................................................................... 34 2.1.8 Bacterial strains ............................................................................................... 36 2.1.9 Eukaryotic cell lines......................................................................................... 36 2.1.10 Enzymes............................................................................................................ 37 2.1.11 Molecular biology kits...................................................................................... 37 2.1.12 Supplier ............................................................................................................ 37 2.2 Molecular biology methods...................................................................................... 39 2.2.1 Plasmid construction........................................................................................ 39 2.2.2 Preparation of complementary DNA (cDNA) libraries ................................... 39 2.2.3 Polymerase chain reaction (PCR).................................................................... 40 2.2.4 Analytical agarose gel electrophoresis............................................................ 42 2.2.5 Purification of DNA from agarose gels and PCR............................................ 42 2.2.6 Restriction digest.............................................................................................. 42 2.2.7 Integration of PCR products into linearized vector backbones ....................... 43 2.2.8 Preparation of chemically competent E.coli.................................................... 43 2.2.9 Transformation of chemically competent E.coli .............................................. 44 2.2.10 Isolation of DNA from bacterial cultures......................................................... 44 2.2.11 Measurement of DNA concentrations .............................................................. 44 2.2.12 Sequencing ....................................................................................................... 45 2.3 Cell biological methods............................................................................................ 45 2.3.1 Cell culture....................................................................................................... 45 6 2.3.2 Plasmid Transfection........................................................................................ 46 2.3.3 siRNA Transfection .........................................................................................
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