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Finally, the four class III fusion proteins resolved (VSV-G, gB of HSV1
and EBV and baculovirus gp64) in spite of their homology of trimeric structure
have some major functional differences arising from their difference of biosyn-
thesis. G protein is the only class III fusion protein whose prefusion structure is
known. The proteins of class fusion III have a combination of the two structural
elements, alpha helix like class I and beta sheet like class II (Backovic
et al
.,
2009; Heldwein
., 2006, 2007)
(Fig. 4.2C). The trimers are maintained by interaction between central alpha
helixes, but each domain of fusion exposes two buckles of internal fusion peptide
placed at the extremity of a long beta sheet. The G protein is the only protein
responsible for the binding and the entry of the VSV. The rhabdovirus VSV
possesses 1200 molecules of the G protein on its surface and forms 400 trimers. In
contrast, the HSV-1 virus incorporates 12 different EnvGP on its surface, of
which 4 are essential for the entry step (gD, gB, and gH/gL) (Turner
et al
., 2006; Kadlec
et al
., 2008; Roche
et al
, 1998).
During their biosynthesis, neither the G protein of VSV nor gB of HSV-1 are
cleaved, and they present internal fusion peptides. However, whereas the G is
functional by itself, the gB envelope glycoprotein alone is not sufficient to induce
the entry of the virus or the membrane fusion. Nevertheless, currently, no precise
interaction between gD, gB, and gH/gL has been identified, even though the gD
ectodomain has been shown to allow the entry of engineered HSV-1 virus
particles that lack gD (that is gD-null mutants; Cocchi
et al.
, 2004). Gp64 is
the major component of the viral envelope, and the sole fusogenic proteins that
are triggered to induce the fusion in the low pH environment of endosomes for
baculovirus. Interestingly, the distinguishing feature between G and gp64 and
any other fusion protein is that they can undergo a reversible conformational
change, unlike class I and most class II fusion proteins, for which the postfusion
conformation is thermodynamically more stable at all pH values, and the con-
formational rearrangement is effectively irreversible. VSV or gp64 exposure to
low pH inactivates the virus, but the fusion activity can be fully recovered when
the pH is raised. It has been proposed that the reversibility of the conformational
change allows G to avoid unspecific activation during transport through the
acidic Golgi vesicles.
As seen in the previous sections, though there is much described
variation in the manner of activation of the fusion proteins and additional
mechanisms await discovery, only three classes of fusion proteins have been
defined so far (Weissenhorn
et al.
., 2007). As previously described, based on the
main structural organization of their EnvGP, the viruses are now assigned to the
class I, II, or III. In parallel, based on the activation mechanism of the fusion
protein, viruses have been classified as pH-dependent or -independent. Interest-
ingly, the relationship between the mechanism of activation of the fusion and
the class of protein of fusion is not correlated. The HIV or Influenza EnvGP are
both class I and yet they have a process of activation that is pH-independent and
et al
