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The Francis Crick Institute Studies on Low Ph-Activated HA2 From The Francis Crick Institute Mill Hill Laboratory, London, UK (Formerly the MRC National Institute for Medical Research) Studies on low pH-activated HA2 from Influenza haemagglutinin A thesis submitted by Roksana Wiktoria Ogrodowicz In partial fulfilment of the requirements of University College London For the degree of Doctor of Philosophy February 2017 1 Declaration I, Roksana Wiktoria Ogrodowicz, declare that the work presented in this thesis was performed in the laboratory of Sir John Skehel & Dr Steven Gamblin in the Division of Molecular Structure and Division of Virology at the Francis Crick Institute, Mill Hill Laboratory, in London, UK (Formerly the MRC National Institute for Medical Research). I confirm that the work presented in this thesis is my own. It has been indicated throughout the text where information has been obtained from other sources. Roksana W. Ogrodowicz Date: 2 Acknowledgements I would like to thank Sir John Skehel and Dr Steven Gamblin for giving me the opportunity to work in the Molecular Structure/Virology lab at the Francis Crick Institute, Mill Hill Laboratory in London, and my thesis committee: Dr Lesley F. Haire, Dr Katrin Rittinger and Dr Peter Rosenthal for their advice and guidance during the course of my study. I am especially thankful to Dr Patrick Collins for help with all aspects of this project. For this I will be forever grateful ;) Thank you! I would like to thank for incredible help I received from my colleagues, particularly Dr Steven Smerdon, Dr Ursula Neu, Dr Xiaoli Xiong, Dr Andrew Purkiss and Dr Jon Wilson for help with X-ray data processing and analysis, Dr Phil Walker for data collection and Baculovirus/insect cell protein expression, Dr Lesley Calder for electron microscopy, Dr Steve Martin for circular dichroism spectroscopy and biolayer interferometry and Dr Yipu Lin & Dr Yan Gu for their assistance with the FI6 antibody neutralization assays. I would like to say thanks to Dr Lasse Stach, Dr Ian Taylor, Dr David Schwefel, Dr Neil Ball and Dr Simon Pennell for their support, advice and patience throughout my Ph.D. 3 Abstract Influenza A haemagglutinin is a surface glycoprotein of Influenza virus, responsible for the initial attachment of the virus to the target cell and, at a later stage, for viral membrane fusion. At the acidic pH of the endosome, the HA molecule undergoes an irreversible structural rearrangement. In consequence, the hydrophobic terminal segments of HA2 are moved to the same end of the refolded molecule, promoting membrane fusion. 16 haemagglutinin subtypes (H1-H16) identified to date can be divided into two groups based on characteristic structural features. The low pH-induced structures of proteolytically prepared and E.coli-expressed fragments of influenza A H3 HA2 (group 2 HA) were previously determined by X-ray crystallography. This study presents structures of proteolytically prepared and recombinantly- expressed fragments of H1 HA2 in a postfusion conformation. Refolded H1 HA2, belonging to group 1 HA, adopts a hairpin-like conformation, similar to that of a rearranged H3 HA2. Structures were compared to the known structures of low pH- activated HA2, to gain a better understanding of the structural differences between the two groups of HA. The data show the structures of the refolded HA2 to be conserved between the HA groups with minor differences. These structural data are supplemented with functional studies involving the cross-reactive FI6 antibody. FI6 antibody binds near the conserved fusion subdomain of the HA molecule and thus interferes with the low pH-triggered conformational change of HA. Additional methods employed in this study, such as limited proteolysis, electron microscopy, biolayer interferometry and MDCK1 cell infection, give insight into the mechanism of FI6 antibody-mediated neutralization, and highlight the differences in infectivity of H1N1 and H3N2 viruses neutralized by the FI6 antibody. 4 Table of contents Declaration ............................................................................................................................... 2 Abstract ...................................................................................................................................... 4 Table of contents .................................................................................................................... 5 List of figures ........................................................................................................................... 8 List of tables ........................................................................................................................... 10 List of abbreviations .......................................................................................................... 11 1. Introduction ...................................................................................................................... 14 1.1 Influenza Viruses ...................................................................................................... 14 1.1.1 Initial isolation ...................................................................................................... 14 1.1.2 Classification and nomenclature of Influenza Viruses ................................ 15 1.1.3 Influenza pandemics and epidemics ................................................................. 16 1.2 Virus morphology and structure ....................................................................... 18 1.3 Virus replication cycle ........................................................................................... 22 1.4 Influenza virus HA and its functions ............................................................... 24 1.4.1 Receptor-binding ................................................................................................... 26 1.4.2 Membrane fusion .................................................................................................. 28 1.4.3 Antigenic evolution ............................................................................................... 30 1.5 Conformational changes in HA leading to membrane fusion ............... 32 1.6 Structural information on the low pH-induced structural refolding of HA obtained to date .................................................................................................. 35 1.6.1 Crystal structure of H3 HA0 precursor ........................................................... 35 1.6.2 Crystal structure of H3 BHA ............................................................................. 35 1.6.3 Crystal structure of postfusion viral H3 TBHA2 ........................................... 38 1.6.4 Crystal structure of E.coli-expressed H3 HA2 ............................................... 40 1.6.5 Crystal structure of E.coli-expressed Influenza B HA2 ............................... 44 1.7 Group-specific structural features of HA ...................................................... 46 1.8 Anti-HA antibodies .................................................................................................. 51 1.8.1 Antibodies blocking receptor-binding ............................................................... 51 1.8.2 Antibodies interfering with the conformational change of HA .................. 52 1.9 Current treatments .................................................................................................. 54 1.10 Objectives for thesis .............................................................................................. 55 2 Materials and Methods .................................................................................................. 56 2.1 Materials ....................................................................................................................... 56 2.1.1 Virus strains .......................................................................................................... 56 2.1.2 Antibodies ............................................................................................................... 56 2.1.3 Reagents .................................................................................................................. 56 2.1.4 Cell lines ................................................................................................................. 56 2.2 Protein expression ................................................................................................... 57 2.2.1 Viral H1 HA2 in a postfusion conformation ................................................... 57 2.2.1.1 Virus infection and growth in embryonated eggs ................................................ 57 2.2.1.2 Virus purification ........................................................................................................ 58 2.2.1.3 Release of HA from purified virus with bromelain ............................................. 59 2.2.1.4 Detergent extraction .................................................................................................. 60 2.2.2 Recombinant H1 HA2 in a low pH conformation .......................................... 61 2.3 Protein preparation ................................................................................................ 63 2.3.1 Quantification of viruses using SDS-PAGE .................................................... 63 2.3.2 Determination of protein concentration .......................................................... 65 2.3.3 SDS-PAGE .............................................................................................................
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