Role of metastability and acidic pH in membrane fusion by tick-borne encephalitis virus.
The envelope protein E of the flavivirus tick-borne encephalitis (TBE) virus is, like the alphavirus E1 protein, a class II viral fusion protein that differs structurally and probably mechanistically from class I viral fusion proteins. The surface of the native TBE virion is covered by an icosahedrally symmetrical network of E homodimers, which mediate low-pH-induced fusion in endosomes. At the pH of fusion, the E homodimers are irreversibly converted to a homotrimeric form, which we have found by intrinsic fluorescence measurements to be more stable than the native dimers. Thus, the TBE virus E protein is analogous to the prototypical class I fusion protein, the influenza virus hemagglutinin (HA), in that it is initially synthesized in a metastable state that is energetically poised to be converted to the fusogenic state by exposure to low pH. However, in contrast to what has been observed with influenza virus HA, this transition could not be triggered by input of heat energy alone and membrane fusion could be induced only when the virus was exposed to an acidic pH. In a previous study we showed that the dimer-to-trimer transition appears to be a two-step process involving a reversible dissociation of the dimer followed by an irreversible trimerization of the dissociated monomeric subunits. Because the dimer-monomer equilibrium in the first step apparently depends on the protonation state of E, the lack of availability of monomers for the trimerization step at neutral pH could explain why low pH is essential for fusion in spite of the metastability of the native E dimer.
Stiasny
K
K
Institute of Virology, University of Vienna, A-1095 Vienna, Austria. karin.stiasny@univie.ac.at
Allison
S L
SL
Mandl
C W
CW
Heinz
F X
FX
D019281:Dimerization; D004669:Encephalitis Viruses, Tick-Borne / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D008561:Membrane Fusion; D013696:Temperature; D014759:Viral Envelope Proteins / Q000737:chemistry*
D008081:Liposomes; D014759:Viral Envelope Proteins