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TECPR2 Cooperates with LC3C to Regulate COPII Dependent ER Export

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TECPR2 Cooperates with LC3C to Regulate COPII Dependent ER Export TECPR2 cooperates with LC3C to regulate COPII dependent ER export Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften vorgelegt beim Fachbereich 15 Biowissenschaften der Johann Wolfgang Goethe – Universität in Frankfurt am Main von Daniela Stadel aus Karlsruhe Frankfurt 2015 D30 vom Fachbereich 15 der Johann Wolfgang Goethe – Universität als Dissertation angenommen. Dekanin: Prof. Dr. Meike Piepenbrink Gutachter: Prof. Dr. Heinz D. Osiewacz Dr. Christian Behrends Datum der Disputation: __________________________________________________________________________ Content 1. Introduction ....................................................................................................................... 9 1.1 Hereditary spastic paraparesis (HSP) ....................................................................... 9 1.1.1 Types and clinical aspects of HSP ..................................................................... 9 1.1.2 Tectonin β-propeller containing protein 2 (TECPR2) ....................................... 11 1.2 The secretory pathway ............................................................................................ 12 1.2.1 COPII coat formation ........................................................................................ 13 1.2.2 ERES ............................................................................................................... 14 1.2.3 Role of SEC24D ............................................................................................... 15 1.2.4 Regulation and assisting factors of the secretory pathway .............................. 15 1.2.5 Role of ER architecture in HSP disease .......................................................... 16 1.3 The endocytic pathway ............................................................................................ 17 1.3.1 HOPS complex ................................................................................................. 18 1.3.2 BLOC-1 complex .............................................................................................. 20 1.4 Autophagy ............................................................................................................... 21 1.4.1 The ubiquitin like conjugation system .............................................................. 23 1.4.2 HOPS and BLOC-1 in autophagy .................................................................... 26 1.5 Aim of the present work ........................................................................................... 27 2. Material and Methods ..................................................................................................... 28 2.1 Materials .................................................................................................................. 28 2.1.1 Chemicals ........................................................................................................ 28 2.1.2 Buffers and media ............................................................................................ 30 2.1.3 Kits ................................................................................................................... 33 2.1.4 Vectors, oligonucleotides and siRNAs ............................................................. 34 2.1.5 Antibodies ........................................................................................................ 38 2.2 Methods ................................................................................................................... 39 2.2.1 Molecular biological methods ........................................................................... 39 2.2.2 Cell biological methods .................................................................................... 43 2.2.3 Protein biochemical methods ........................................................................... 45 2.2.4 Biophysical and structural methods ................................................................. 49 I __________________________________________________________________________ 2.2.5 Phenotypical assays ........................................................................................ 51 3. Results ............................................................................................................................ 53 3.1 TECPR2 associates and colocalizes with SEC24D, BLOC-1 and HOPS ............... 53 3.2 TECPR2 binds LC3 and GABARAP proteins in a LIR-dependent manner ............. 57 3.3 Association with SEC24D, BLOC-1 and HOPS requires LC3 binding of TECPR2 . 66 3.4 TECPR2 depletion destabilizes SEC24D, HOPS and BLOC-1 ............................... 69 3.5 Loss of TECPR2 compromises ERES .................................................................... 73 3.6 TECPR2 is required for ER export .......................................................................... 77 3.7 TECPR2 depletion affects ER morphology ............................................................. 81 3.8 TECPR2 contributes to autophagosome formation ................................................. 83 4. Discussion ...................................................................................................................... 90 4.1 Model: TECPR2 as scaffold for endomembrane signaling ...................................... 90 4.2 Assembly of the inner COPII coat ........................................................................... 92 4.3 HOPS ...................................................................................................................... 95 4.4 BLOC-1 ................................................................................................................... 96 4.5 LIR motif of TECPR2 and binding preference ......................................................... 97 4.6 ER export and autophagy ........................................................................................ 98 4.7 ER maintenance and neurodegeneration .............................................................. 101 4.8 Concluding remarks and future perspectives ........................................................ 103 5. References ................................................................................................................... 106 Zusammenfassung .............................................................................................................. 118 Danksagung ......................................................................................................................... 123 Curriculum vitae ................................................................................................................... 125 Publications ......................................................................................................................... 126 Presentations at conferences .............................................................................................. 127 Eidesstattliche Erklärung ..................................................................................................... 128 II __________________________________________________________________________ Abbreviations µ micro A Ampere Å Ångström aa aminoacid ABC ammonium bicarbonate ACN acetonitril ACTBL2 Beta-actine-like protein 2 AIM ATG interacting motif ALFY autophagy-linked FYVE protein α alpha, anti ANP32A Acidic leucine-rich nuclear phosphoprotein 32 family member A APS ammonium persulfate APSM average peptide spectral matches Asp aspartic acid ATG autophagy-related protein ATL1, SPG3A atlastin 1 BafA1 Bafilomycin A1 BCA bicinchoninic acid β beta BLOC-1 biogenesis of lysosome-related organelles complex 1 BLOS-1/2/3 biogenesis of lysosome-related organelle complex subunit-1/2/3 Btz Bortezomib °C degree celsius C.elegans Caenorabditis elegans CALR calreticulin CKAP4, CLIMP63 cytoskeleton-associated protein 4 CMA chaperone-mediated autophagy CMV cytomegalo virus CNO cappuccino COL10A1,COL1A1 collagen alpha-1 chain COPI/II coat protein complex I/II CORVET class c core vacuole/endosome tethering 1 __________________________________________________________________________ CPNC condensed perinuclear cluster CSP chemical shift perturbation C-terminal carboxy terminal D Aspartic acid DAPI 4,6-diamidin-2-phenylindol DAVID Database for Annotation, Visualization, and Integrated Discovery del deletion DFCP1 double FYVE-contining protein 2 DIC dynein intermediate chain DKFZ Deutsches Krebsforschungszentrum DMEM Dulbeccos modified eagle medium DMSO dimethylsulfoxide DNA deoxyribonucleic acid DTBP dimethyl-3,3-dithiobispropionimidate DTNBP1 dysbindin 1 DTT dithiotreitol DUB deubiquitinase E.coli Escherichia coli e.g. latin: exemplar gratia, english: for example E1/2/3 enzyme ECL Enhanced chemilumiscence EDTA ethylenediaminetetraacetic acid EGFR epidermal growth factor receptor EM Electron microscopy ER endoplasmic reticulum ERES ER exit sites ERGIC ER-to-Golgi intermediate compartment ESCRT escort complex FRAP fluorescence recovery after photobleaching FBS fetal bovine serum fig. figure FIP200, RB1CC1 RB1-inducible coiled-coil protein 1 FYCO1 FYVE and coiled-coil domain-containing protein 1 g gravity 2 __________________________________________________________________________ GABA gamma aminobutyric acid GABARAP gamma-aminobutyric acid receptor-associated protein GABARAPL1/2 gamma-aminobutyric acid receptor-associated protein-like1/2 GATE-16 gamma-aminobutyric acid receptor-associated protein-like 2 GAP guanosine triphosphatase activting protein GAT1
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