The envelope protein E of the flavivirus tick-borne encephalitis (TBE) viru
s is, like the alphavirus El 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 icosahedra
lly symmetrical network of E homodimers, which mediate low-pH-induced fusio
n in endosomes. At the pH of fusion, the E homodimers are irreversibly conv
erted 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 inf
luenza virus hemagglutinin (HA), in that it is initially synthesized in a m
etastable state that is energetically poised to be converted to the fusogen
ic state by exposure to low pH. However, in contrast to what has been obser
ved with influenza virus HA, this transition could not be triggered by inpu
t of heat energy alone and membrane fusion could be induced only when the v
irus was exposed to an acidic pH. In a previous study we showed that the di
mer-to-trimer transition appears to be a two-step process involving a rever
sible dissociation of the dimer followed by an irreversible trimerization o
f the dissociated monomeric subunits. Because the dimer-monomer equilibrium
in the first step apparently depends on the protonation state of E, the la
ck of availability of monomers for the trimerization step at neutral pH cou
ld explain why low pH is essential for fusion in spite of the metastability
of the native E dimer.