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

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Presentation transcript:

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 Metastable fusion proteins

Entry of Enveloped Viruses Receptor- triggered fusion Metastable fusion proteins

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

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

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

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

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

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

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

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

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

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

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

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

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

Conversion of Flavi E into Hairpin-Like Structure

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

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

Viral Cell Fusion Erice, June

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.....