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Investigating Novel Binding Partners of Exocyst Member Sec8 in the Fission

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Investigating Novel Binding Partners of Exocyst Member Sec8 in the Fission Identifying novel interaction partners of the exocyst member Sec8 in the fission yeast Schizosaccharomyces pombe Submitted by Lauren Adams to the University of Exeter as a thesis for the degree of Masters by Research in Biological Sciences In September 2017 This thesis is available for Library use on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. I certify that all material in this thesis which is not my own work has been identified and that no material has previously been submitted and approved for the award of a degree by this or any other University. Signature: ………………………………………………………….. 1 Acknowledgements I would like to thank Dr Helen Dawe and Dr Isabelle Jourdain for being utterly brilliant supervisors. I would also like to thank Connor Horton for his continued assistance, Dr Kate Heesom (Proteomics Facility, University of Bristol), Tina Schrader (University of Exeter) for kindly providing the Mitotracker stain, and the Biosciences Department (University of Exeter) for partially funding this project. 2 Abstract The exocyst is a complex of proteins classically known for its role in tethering secretory vesicles during exocytosis, but it has since been shown to participate in a whole host of other cellular processes. Several human patients have been discovered in whom mutations in the exocyst appear to cause disease, but the underlying mechanisms are still poorly understood. This highlights an urgent need to better characterise these proteins. The exocyst complex is conserved in the fission yeast Schizosaccharomyces pombe, which is an ideal model eukaryote in which to examine conserved biological mechanisms. In this study, I used GFP-Trap combined with qualitative proteomics to reassess the role of exocyst component Sec8. Unexpectedly, this uncovered putative novel associations with both the nuclear envelope and the mitochondrial envelope. Using live-cell imaging, I further showed that cells expressing mutated Sec8 displayed altered mitochondrial morphology and a significant reduction in mitochondrial fusion. This indicates that Sec8 is somehow involved in mitochondrial distribution and dynamics, a role which has not been previously described. This may provide further insight into the role of the exocyst in both normal and pathological conditions. Keywords: GFP-Trap, Exocyst, mitochondria 3 Table of Contents Acknowledgements .................................................................................................................... 2 Abstract ........................................................................................................................................ 3 Table of Contents ...................................................................................................................... 4 List of Figures .............................................................................................................................. 6 List of Tables ............................................................................................................................... 6 Abbreviations used in this study ............................................................................................... 7 A multitude of cellular roles for the exocyst complex .......................................... 8 1.1 Exocytosis .................................................................................................................. 8 1.1.1 Functions of Exocytosis ..................................................................................... 8 1.1.2 Stages of Exocytosis .......................................................................................... 9 1.2 The Exocyst Complex ........................................................................................... 11 1.2.1 Discovery ........................................................................................................... 11 1.2.2 Role in Exocytosis ............................................................................................ 12 1.2.3 Biochemical & Structural Studies ................................................................... 13 1.2.4 Evolutionary Conservation .............................................................................. 13 1.3 Cellular Roles of Sec8 ........................................................................................... 16 1.3.1 Discovery and Conservation ........................................................................... 16 1.3.2 Sec8 is Directly Involved in the Secretion of Multiple Proteins .................. 19 Neuronal Secretion ....................................................................................................... 19 Insulin Secretion ........................................................................................................... 21 Extracellular Matrix Degradation ................................................................................ 21 1.3.3 Through Its Role in Exocytosis, Sec8 Controls Cell Division and Polarity ........................................................................................................ 22 Cytokinesis .................................................................................................................... 22 Neuronal Polarity .......................................................................................................... 23 Epithelial Polarity .......................................................................................................... 24 1.3.4 Emerging Non-conventional Roles of Sec8 .................................................. 24 Macroautophagy ........................................................................................................... 25 Apoptosis ....................................................................................................................... 25 Cell Cycle Control ......................................................................................................... 26 DNA Repair ................................................................................................................... 27 Cell Migration ................................................................................................................ 29 4 1.3.5 The Exocyst can Perform Multiple Different Roles in Order to Orchestrate a Cellular Function ................................................................. 29 1.4 Perspectives and Outstanding Questions ....................................................... 32 1.4.1 The Possibility of Sub-complexes .................................................................. 32 1.4.2 Elucidating the Roles of Exocyst Components ............................................ 34 1.4.3 Undiscovered Functions .................................................................................. 35 1.5 Aims of This Study ................................................................................................. 36 Methods ................................................................................................................................... 37 2.1. Yeast Culture and Genetics ................................................................................. 37 2.1.1. Media and Culture ............................................................................................ 37 2.1.2. Crossing Strains................................................................................................ 37 2.2. GFP-Trap ................................................................................................................... 38 2.2.1. Protein Extraction and Immuno-precipitation ............................................... 38 2.2.2. Western Blotting................................................................................................ 41 2.2.3. Proteomics Analysis ......................................................................................... 41 2.3. Cell Biology .............................................................................................................. 43 2.3.1. Microscopy and Image Acquisition ................................................................ 43 2.3.2. Image Analysis .................................................................................................. 44 2.3.3. Statistical Analyses .......................................................................................... 46 Identifying Novel Interaction Partners of the Exocyst Member Sec8 ........... 47 3.1. GFP-Trap Identifies 136 Interaction Partners of Sec8 .................................. 47 3.2. Clustering of the Sec8 Interaction Partners Reveals Nucleus-associated Proteins .............................................................................. 51 3.3. Perturbation of Sec8 Affects Nuclear Volume, but Not Positioning ......... 56 3.4. Clustering of the Sec8 Interaction Partners Reveals Mitochondria-associated Proteins .................................................................... 58 3.5. Perturbation of Sec8 Causes a Change in Mitochondrial Morphology .... 61 3.6. Perturbation of Sec8 Causes a Reduction in Mitochondrial Fusion......... 62 Discussion ............................................................................................................................. 66 4.1. Evaluating the Success of the GFP-Trap ......................................................... 66 4.2. Novel nuclear roles for Sec8 ..............................................................................
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