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Structure and Function of Large Molecular Assemblies Viral Cell Fusion Erice, June 15, 2006

Structure and Function of Large Molecular Assemblies Viral Cell Fusion Erice, June 15, 2006. Ligand-induced nonfusogenic dissolution of a viral membrane: Vaccinia virus (Law et al., PNAS 103, 2006). Entry of Enveloped Viruses. Metastable fusion proteins. Entry of Enveloped Viruses.

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Structure and Function of Large Molecular Assemblies Viral Cell Fusion Erice, June 15, 2006

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  1. Structure and Function of Large Molecular AssembliesViral Cell FusionErice, June 15, 2006

  2. Ligand-induced nonfusogenic dissolution of a viral membrane: Vaccinia virus (Law et al., PNAS 103, 2006)

  3. Entry of Enveloped Viruses Metastable fusion proteins

  4. Entry of Enveloped Viruses Metastable fusion proteins

  5. Entry of Enveloped Viruses Receptor-triggered fusion Metastable fusion proteins

  6. Entry of Enveloped Viruses Receptor-triggered fusion (HIV, Herpes, …) Metastable fusion proteins

  7. Entry of Enveloped Viruses Receptor-mediated endocytosis Receptor-triggered fusion (HIV, Herpes, …) Metastable fusion proteins

  8. Entry of Enveloped Viruses Receptor-mediated endocytosis Receptor-triggered fusion (HIV, Herpes, …) Metastable fusion proteins Endosomes

  9. Entry of Enveloped Viruses Receptor-mediated endocytosis Receptor-triggered fusion (HIV, Herpes, …) Metastable fusion proteins H+ Low-pH-mediated fusion (Influenza virus, Flaviviruses, Alphaviruses, …)

  10. Entry of Enveloped Viruses Receptor-mediated endocytosis Receptor-triggered fusion (HIV, Herpes, …) Metastable fusion proteins H+ Low-pH-mediated fusion (Influenza virus, Flaviviruses, Alphaviruses, …) H+

  11. Entry of Enveloped Viruses Receptor-mediated endocytosis Receptor-triggered fusion (HIV, Herpes, …) Metastable fusion proteins H+ Low-pH-mediated fusion (Influenza virus, Flaviviruses, Alphaviruses, …) H+ Some retroviruses require both triggers

  12. Morphological Types of Enveloped Viruses ‚Spiky‘; Pleomorphic Icosahedral Alpha viruses Flavi viruses Influenza viruses (ortho-, paramyxo-, retro-, filo-, rhabdo-, corona- ….viruses)

  13. Viral Fusion Proteins Class I: Orthomyxoviruses (Influenza Virus Hemagglutinin), Paramyxoviruses, Retroviruses, Filoviruses, Coronaviruses Class II: Flaviviruses (Tick-borne encephalitis TBE Virus E Protein), Alphaviruses N-terminal (N-proximal) Fusion Peptide Internal Fusion Peptide Loop COO- COO-

  14. Trigger Trigger Cleavage Cleavage Viral Fusion Proteins: Generation of Metastable Structures Class I: Orthomyxoviruses (Influenza Virus Hemagglutinin), Paramyxoviruses, Retroviruses, Filoviruses, Coronaviruses Inactive precursor Homotrimer Metastable State Post-fusion (Hairpin) Class II: Flaviviruses (Tick-borne encephalitis TBE Virus E Protein), Alphaviruses Inactive Precursor Heterodimer Post-fusion (Hairpin) Metastable State

  15. Class I Fusion Jardetzky and Lamb, 2004; Nature 427 Class II Fusion Modis et al., 2004; Nature 427

  16. Different Sites of Proteolytic Activationof Viral Fusion Proteins to Generate Metastable Confomation Influenza Virus Site B Endocytosis Site A Site C TGN HIV Influenza Virus Flavivirus Alphavirus Ebola Virus SARS Virus Nipah Virus H+ Endosome ER/ Golgi

  17. Ilaria Capua, Italien Fowl plague: H5 or H7 (Italy 1999: H7N1) Ilaria Capua, Italien

  18. Viral Fusion Proteins Class I: Orthomyxoviruses (Influenza Virus Hemagglutinin), Paramyxoviruses, Retroviruses, Filoviruses, Coronaviruses Class II: Flaviviruses (Tick-borne encephalitis TBE Virus E Protein), Alphaviruses A new class of viral fusion proteins? no cleavage activation reversible conformational changes

  19. Conversion of Flavi E into Hairpin-LikeStructure

  20. Trigger Trigger Cleavage Cleavage Viral Fusion Proteins: Generation of Metastable Structures Class I: Orthomyxoviruses (Influenza Virus Hemagglutinin), Paramyxoviruses, Retroviruses, Filoviruses, Coronaviruses Inactive Precursor Metastable State Post-fusion (Hairpin) Class II: Flaviviruses (Tick-borne encephalitis TBE Virus E Protein), Alphaviruses Post-fusion (Hairpin) Inactive Precursor Metastable State

  21. Class I and II Post-Fusion Structures Class I Class II stem fusion peptide membrane anchor Jahn et al., 2003 Cell 112

  22. Viral Cell Fusion Erice, June 15 2006

  23. Influenza HA: Cleavage site as a virulence determinant • H7N1 Italy 1999: Low pathogenic vs. highly pathogenic avian virus • . . . . . . . . . P E I P K G R -//- G L F . . . . . • . . . . . . . . . P E I P K G R K R K T R -//- G L F . . . . .

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