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Gadalla Online.Pdf Aus dem Institut für Virologie des Fachbereichs Veterinärmedizin der Freien Universität Berlin Identification of ZDHHC enzymes catalyzing acylation of influenza virus Hemagglutinin Inaugural-Dissertation zur Erlangung des Grades eines Doctor of Philosophy (PhD) an der Freien Universität Berlin vorgelegt von Mohamed Rasheed Abdelalim Mohamed Gadalla Tierarzt aus Kairo /Ägypten Berlin 2020 Journal-Nr.: 4189 Gedruckt mit Genehmigung des Fachbereichs Veterinärmedizin der Freien Universität Berlin Dekan: Univ.-Prof. Dr. Jürgen Zentek Erster Gutachter: PD Dr. Michael Veit Zweiter Gutachter: Univ.-Prof. Dr. Klaus Osterrieder Dritter Gutachter: Univ.-Prof. Dr. Hafez Mohamed Hafez Deskriptoren (nach CAB-Thesaurus): Man, Cell lines, Cell Culture, Respiratory system, Influenza viruses, Hemagglutinins, Matrix protein, CRISPR-Cas9, Transmembrane proteins, Fatty acids, Stearic acid, Palmitate, Polymerase chain reaction, SDS-PAGE, Western Blotting, MALDI-TOF Tag der Promotion: 25.02.2020 Bibliografische Information der Deutschen Nationalbibliothek Die Deutsche Nationalbibliothek verzeichnet diese Publikation in der Deutschen Nationalbi- bliografie; detaillierte bibliografische Daten sind im Internet über <https://dnb.de> abrufbar. ISBN: 978-3-96729-040-0 Zugl.: Berlin, Freie Univ., Diss., 2020 Dissertation, Freie Universität Berlin D188 Dieses Werk ist urheberrechtlich geschützt. Alle Rechte, auch die der Übersetzung, des Nachdruckes und der Vervielfältigung des Buches, oder Teilen daraus, vorbehalten. Kein Teil des Werkes darf ohne schriftliche Genehmigung des Verlages in irgendeiner Form reproduziert oder unter Verwendung elektronischer Systeme verarbeitet, vervielfältigt oder verbreitet werden. Die Wiedergabe von Gebrauchsnamen, Warenbezeichnungen, usw. in diesem Werk berechtigt auch ohne besondere Kennzeichnung nicht zu der Annahme, dass solche Namen im Sinne der Warenzeichen- und Markenschutz-Gesetzgebung als frei zu betrachten wären und daher von jedermann benutzt werden dürfen. This document is protected by copyright law. No part of this document may be reproduced in any form by any means without prior written authorization of the publisher. alle Rechte vorbehalten | all rights reserved © Mensch und Buch Verlag 2020 Choriner Str. 85 - 10119 Berlin [email protected] – www.menschundbuch.de Dedication To my Great Parents To my wonderful wife ♥Asmaa ♥ To my Little Kids ♥Ziad &Layan ♥ To my Brother (Ahmed) To my Beloved Sisters (Heba & Dina) Table of contents Table of contents ................................................................................................................................. I Abbreviations ...................................................................................................................................... V List of Figures .................................................................................................................................. VII List of Tables ................................................................................................................................... VIII 1. Introduction ..................................................................................................................................... 1 1.1. Influenza A virus ....................................................................................................... 1 1.1.1. Virus taxonomy and nomenclature ................................................................................. 1 1.1.2 Virus structure and genome organization ....................................................................... 2 1.1.3. Replication cycle ................................................................................................................ 3 1.1.4 Hemagglutinin glycoprotein (HA) ...................................................................................... 7 1.1.4.1. Structure and function of HA ..................................................................................... 7 1.1.4.2. Intracellular transport and processing ..................................................................... 9 1.2. Acylation/Palmitoylation of proteins ......................................................................10 1.2.1. S-acylated proteins of viruses pathogenic for human ................................................ 10 1.2.1.1. S-acylated proteins of Influenza viruses ............................................................... 12 1.2.1.2. S-acylation of proteins from other viruses ............................................................. 14 1.3. Enzymology of S-acylation. .....................................................................................17 1.3.1. Crystal structures of ZDHHC enzymes.. ....................................................................... 20 1.3.2. Lipid- and protein substrate specificities of ZDHHC proteins ...............................21 1.3.3. Acylprotein thioesterases and other enzymes that deacylate proteins .................22 1.4. Methods to study s-acylation of proteins ...............................................................23 I. Radioactive labeling............................................................................................................. 23 II. Acyl biotin exchange (ABE) and Acyl-resin assisted capture (Acyl-RAC). ................23 III. Click Chemistry based methods (Radioactive free labeling) ....................................24 1.4.1. Methods to identify ZDHHC substrate pairs. ........................................................25 2. Aim of the study ........................................................................................................................... 26 3. Materials and Methods ............................................................................................................... 27 3.1. Materials ...................................................................................................................27 3.1.1. Chemicals, consumables and equipment .................................................................... 27 3.1.1.1. Chemicals .................................................................................................................. 27 3.1.1.2. Consumables ................................................................................................29 3.1.1.3. Equipment .................................................................................................................. 30 3.1.1.4. Software ..................................................................................................................... 31 3.1.1.5. Enzymes and markers ...................................................................................32 3.1.1.6. Kits ................................................................................................................33 I 3.1.2. Primers ................................................................................................................33 3.1.2.1. Primers used for generation of HA acylation mutant by reverse genetics.......33 3.1.2.2. Primers used for expression profiling of Human ZDHHCs ..............................34 3.1.2.3. Guide RNA sequences and screening primers used for generation of CRISPR/Cas9 Knockout cell lines ..............................................................................35 3.1.2.4. Sequencing Primers used for validation of gRNA cloning in CRISPR vecto rs...36 3.1.3. Antibodies............................................................................................................36 3.1.4. Prepared solutions and Buffers ............................................................................37 3.2. Methods ....................................................................................................................39 3.2.1. Molecular biology methods ............................................................................................ 39 3.2.1.1. Preparation of chemically competent E. coli......................................................... 39 3.2.1.2. Transformation of competent bacterial cells ......................................................... 39 3.2.1.3. Plasmid purification .......................................................................................39 3.2.1.4. Quick Change Site directed mutagenesis ............................................................. 40 3.2.1.5. Screening and Sequencing Polymerase chain reaction (PCR) ......................42 3.2.1.6. Agarose gel electrophoresis ..........................................................................42 3.2.1.7. DNA extraction or clean up from agarose gel ...................................................... 42 3.2.1.8. CRISPR/Cas9 technology ....................................................................................... 43 3.2.1.8.1. CRISPR/Guide RNA annealing and vector cloning . ................................45 3.2.1.9. Quantitative Real-time PCR (qPCR).... ..........................................................46 3.2.1.10. siRNA transfection and Knockdown.... .........................................................47 3.2.2. Cell culture and micro scopy ...... ..........................................................................48 3.2.2.1. Cultivation and maintenance of mammalian cells..... ......................................48 3.2.2.2. Freezing and thawing of cells.........................................................................48 3.2.2.3. Transfection.... ...............................................................................................48
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