structure and function of large molecular assemblies viral cell fusion erice, june 15, 2006
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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 ProteinsClass 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
HeterodimerMetastable State
Post-fusion (Hairpin)
Post-fusion (Hairpin)
Trigger
Cleavage
Cleavage
Trigger
Class I FusionClass I Fusion
Class II FusionClass II Fusion
Modis et al., 2004; Nature 427
Jardetzky and Lamb, 2004; Nature 427
Different Sites of Proteolytic Activationof Viral Fusion Proteins to Generate Metastable Confomation
Endocytosis
Endosome
TGN
Influenza Virus
Ebola VirusSARS VirusNipah Virus
HIVInfluenza VirusFlavivirusAlphavirus
Site B
Site ASite C
H+
ER/ Golgi
Ilaria Capua, Italien
Ilaria Capua, Italien
Fowl plague: H5 or H7
(Italy 1999: H7N1)
Viral Fusion ProteinsClass 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-LikeStructure
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 Metastable State
Inactive Precursor Metastable State
Post-fusion (Hairpin)
Post-fusion (Hairpin)
Trigger
Cleavage
Cleavage
Trigger
Class I and II Post-Fusion StructuresClass I and II Post-Fusion Structures
Class IClass I Class IIClass II
Jahn et al., 2003Cell 112
membrane anchor
fusion peptide
stem
Viral Cell FusionViral Cell Fusion
Erice, June 15 2006
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 . . . . .