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1.4 yves gaudin






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  • Description de l’espace conformationnel
  • Transition aps terminée Orientation du segment qui relie le tm domaine

1.4 yves gaudin 1.4 yves gaudin Presentation Transcript

  • Understanding the rhabdovirus fusion machinery Perspectives opened by dynamic structural virology Molecular and Structural Virology Laboratory CNRS – Gif sur Yvette Yves Gaudin CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
  • Rhabdovirus entry into the host cell Prototypes : rabies virus and VSV Enveloped viruses with a typical bullet shape Glycoprotein G mediates viral entry Endosome acidification Membrane fusion Virion endocytosis Receptor recognition
  • The membrane fusion pathway Complete fusion Stalk Hemifusion Fusion Pore Class I Paramyxovirus F Influenza HA HIV gp160 Class II Alphavirus E1 Flavivirus E Native or prefusion conformation Energy Final or postfusion conformation Fusion machineries
  • Rhabdovirus glycoprotein G: The prototype of the third class How does it work ? Internal fusion loops Transmembrane domain 446 466 495 CHO CHO pH-dependent equilibrium between these different states Prefusion state Activated state Postfusion state Receptor recognition Membrane interaction pH >7 pH < 6.5 pH 7.5 pH 5.5 One glycoprotein Several conformations
  • Visualization of individual fusion events pH 7.5
    • Identification of two distinct steps
    • during membrane fusion
    • Libersou et al. J. Cell Biol. 2010
    LIPO LIPO pH 5.5
  • Crystalline structures of VSV G TM Trimers Prefusion Postfusion Roche et al. Science 2006 ; Science 2007 Membrane Forme préfusion Protomers Prefusion Postfusion
  • Target membrane Viral membrane
  • The conformational change pathway Trimeric prefusion state (high pH) Trimeric postfusion state (low pH) Fusion loops Transmembrane domains * * Tomography Cristallography Tomography Cristallography EM SAXS Decreasing pH
  • First structure of intermediates
    • Chandipura virus (outbreaks of deadly encephalitis in India)
    • Two different monomers in the asymetric unit !
    1 1 2 2 VSV G postfusion Late intermediate VSV G prefusion Fusion loops. TM domains. Early intermediate
  • Structural virology: a french « savoir faire »
      • Class II fusion proteins of Chikungunya virus ( Felix Rey , Institut Pasteur)
      • Replication complex of influenza and Mononegavirales , HIV structural biology ( Rob Ruigrok , Winfried Weissenhorn , UVHCI, Grenoble)
      • Replication complex of positive strand RNA viruses such as Dengue virus, West Nile virus, SARS coronavirus ( Bruno Canard , AFMB, Marseille)
  • Perspectives
    • Powerful hybrid approaches (Cristallography, EM, SAXS, NMR…) in structural virology allow:
    • Access to the dynamics of complex viral machineries
    • Determination of the structure of intermediates that can constitute new targets for antiviral strategies