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Glycoprotein Interactions in the Assembly of Hantaviruses

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Glycoprotein Interactions in the Assembly of Hantaviruses Research Programs Unit, Infection Biology Research Program Department of Virology Haartman Institute, Faculty of Medicine University of Helsinki Glycoprotein Interactions in the Assembly of Hantaviruses Jussi Hepojoki ACADEMIC DISSERTATION To be publicly represented and discussed, with the permission of the Faculty of Medicine of the University of Helsinki, in the Small Lecture Hall, Haartman Institute, Haartmaninkatu 3, Helsinki, on the 9th of December 2011, at 12 o’clock. Helsinki 2011 Supervisors: Docent Hilkka Lankinen Peptide and Protein Laboratory Department of Virology Haartman Institute University of Helsinki and Professor Emeritus Antti Vaheri Department of Virology Haartman Institute University of Helsinki Reviewers: Docent Tero Ahola Institute of Biotechnology University of Helsinki and Docent Varpu Marjomäki Department of Biological and Environmental Science University of Jyväskylä Opponent: Professor Richard M Elliott School of Biology University of St Andrews Scotland, UK ISBN 978-952-10-7333-5 (paperback) ISBN 978-952-10-7334-2 (PDF, available at http://ethesis.helsinki.fi) Layout by John Smackriver Printed at Helsinki by Unigrafia Oy, Helsinki University Print Helsinki 2011 “In the field of observation chance favors only the prepared mind.” -Louis Pasteur (1822-1895) CONTENTS LIST OF ORIGINAL PUBLICATIONS ................................................. 6 ABBREVIATIONS ............................................................................... 7 ABSTRACT ......................................................................................... 8 TIIVISTELMÄ (SUMMARY IN FINNISH) ........................................... 10 REVIEW OF THE LITERATURE ....................................................... 12 DISCOVERY AND HISTORY OF HANTAVIRUSES ................................................................ 12 CLASSIFICATION OF HANTAVIRUSES.............................................................................. 12 Transmission of hantaviruses ................................................................................ 13 PATHOGENESIS OF HANTAVIRUSES............................................................................... 13 Clinical manifestations of HFRS ............................................................................. 13 Clinical manifestations of HCPS............................................................................. 14 Innate and cellular immune response to hantaviruses ............................................. 14 Humoral immune response to hantaviruses ............................................................ 14 GENOME AND REPLICATION OF HANTAVIRUSES .............................................................. 15 RNA replication ..................................................................................................... 16 mRNA synthesis ..................................................................................................................................16 vRNA and cRNA synthesis ..................................................................................................................17 STRUCTURE OF HANTAVIRUS PARTICLE ......................................................................... 17 PROTEIN COMPONENTS OF HANTAVIRUS ....................................................................... 18 N protein ............................................................................................................... 18 Oligomerization of N protein.................................................................................................................18 Interaction with RNA and formation of the RNP complex .....................................................................19 Interactions with other viral proteins .....................................................................................................20 Interactions with cellular proteins .........................................................................................................20 Non-structural protein (NSs) .................................................................................. 22 Glycoprotein precursor, GPC (Gn and Gc glycoproteins) ........................................ 22 Folding and maturation of Gn and Gc ..................................................................................................23 Glycosylation of Gn and Gc .................................................................................................................24 Fusogenic activity of the GPC ..............................................................................................................24 Formation of spike complex .................................................................................................................25 Cytoplasmic tails (CTs) of Gn and Gc ..................................................................................................25 RNA-dependent RNA-polymerase (RdRp, L Protein) .............................................. 27 ENTRY OF VIRUSES .................................................................................................... 28 Entry of hantaviruses ............................................................................................. 28 VIRAL FUSION PROTEINS ............................................................................................. 29 Class I fusion proteins ........................................................................................... 30 Class II fusion proteins .......................................................................................... 30 Class III fusion proteins ......................................................................................... 30 ASSEMBLY OF HANTAVIRUS PARTICLE ........................................................................... 30 AIMS OF THE STUDY ....................................................................... 32 MATERIALS AND METHODS .......................................................... 33 CELLS AND VIRUS CULTIVATION (I-IV) ........................................................................... 33 PURIFICATION OF VIRUSES (I-IV) ................................................................................. 33 ANTIBODIES (I-IV) ...................................................................................................... 34 IMMUNOPRECIPITATION AND PULL-DOWN (I,III,IV) .......................................................... 34 SDS-PAGE AND IMMUNOBLOTTING (I,III,IV) ................................................................. 35 PEPTIDE SYNTHESIS (I,III,IV)....................................................................................... 35 INTERACTION SITE MAPPING (I,III) ................................................................................ 35 CRYO ELECTRON MICROSCOPY (I,II) ............................................................................ 36 ELECTRON CRYOTOMOGRAPHY (II) .............................................................................. 37 SEDIMENTATION IN SUCROSE GRADIENT (I) ................................................................... 37 GEL-FILTRATION CHROMATOGRAPHY (I,III).................................................................... 37 MASS SPECTROMETRY, MS (I, III, IV) ........................................................................... 37 RESULTS ......................................................................................... 38 PURIFICATION OF VIRUSES (I-IV) ................................................................................. 38 INTERACTIONS BETWEEN THE STRUCTURAL COMPONENTS OF VIRION (I-III)....................... 38 Gn-Gc interaction (I and II) .................................................................................... 38 Gn-Gn interaction (I and II) .................................................................................... 40 Gc-Gc interaction (I and II) .................................................................................... 41 The spike complex (I and II) .................................................................................. 42 Spike-RNP interaction (II and III) ........................................................................... 42 THE MORPHOLOGY AND STRUCTURE OF VIRION (I AND II)................................................ 44 INTERACTION BETWEEN GALECTIN-3 BINDING PROTEIN AND VIRION (IV) ........................... 44 DISCUSSION .................................................................................... 46 INTERACTIONS BETWEEN GLYCOPROTEINS ................................................................... 46 STRUCTURE OF THE GLYCOPROTEIN SPIKE COMPLEX ..................................................... 47 THE FUSOGENIC POTENTIAL OF GC .............................................................................. 54 INTERACTION BETWEEN SPIKE AND RNP ...................................................................... 55 ASSEMBLY OF VIRIONS ............................................................................................... 57 INTERACTION OF TULV WITH 90K/MAC-2BP ................................................................ 60 90K/MAC-2BP IN ACUTE PUUV INFECTION .................................................................. 60 CONCLUDING REMARKS AND FUTURE PROSPECTS ................ 62 ACKNOWLEDGEMENTS ................................................................. 64 REFERENCES .................................................................................
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