Role of metastability and acidic pH in membrane fusion by tick-borne encephalitis virus

Citation
K. Stiasny et al., Role of metastability and acidic pH in membrane fusion by tick-borne encephalitis virus, J VIROLOGY, 75(16), 2001, pp. 7392-7398
Citations number
31
Categorie Soggetti
Microbiology
Journal title
JOURNAL OF VIROLOGY
ISSN journal
0022538X → ACNP
Volume
75
Issue
16
Year of publication
2001
Pages
7392 - 7398
Database
ISI
SICI code
0022-538X(200108)75:16<7392:ROMAAP>2.0.ZU;2-O
Abstract
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.