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-dependent, respectively, for the entry of the virus. Similarly, the class III fusion
proteins enclose the Herpes virus simplex 1 (HSV-1) gB protein and the rhab-
dovirus VSV-G protein that are pH-independent and pH-dependent, respective-
ly, for their activation. So far, all the class II fusion proteins have been pH-
dependent for their activation.
E. Common refolding process
Although there are notable differences between the activation processes, the
structural motives used, and the initial oligomeric states of the fusion proteins
(the native trimeric conformation of class I and III proteins in opposition to the
homo- or heterodimers of the class II fusion proteins), the common features of the
final structures obtained after fusion seem to suggest some generic mechanism of
conformational changes common to all EnvGP of enveloped viruses (see Fig. 4.2).
First, the activation of the fusion protein following the interaction with
the cellular receptor(s), coupled or not to the exposure to the acid environment
of the endosomes, exposes the fusion peptide that is projected toward the top of
the glycoprotein, allowing the initial interaction with the cellular target mem-
brane. For class I fusion proteins, the proposed model indicates that the transi-
tion of conformation requires the transformation of a part of the molecule in
alpha helix and the association of this in three helixes bundle (named the “coiled
coil”; Weissenhorn
., 2007). For retroviruses, this movement allows a loop-
to-helix transition of a polypeptide segment of TM that was previously buried
underneath the SU heads, projecting the fusion peptide
et al
100
˚
toward the
target membrane, where it inserts irreversibly. In the case of class I fusion
proteins like retroviruses, this occurs by a “spring-loaded” mechanism. This
initial change is proposed to result in a “prehairpin intermediate,” an extended
structure that is anchored both in the target membrane by the fusion peptide and
in the virus membrane by the TM transmembrane segment. For the class II fusion
proteins, the projection of the fusion peptide requires the dissociation of the
hetero- or homodimers and modifications in the “hinge region” unstructured
before conformational changes (Stiasny and Heinz, 2006). For the class III
(Roche
., 2008), similarly to the fusion proteins of class I, the exhibition of
the fusion peptide requires a rearrangement of the domains mediated by modifi-
cation of the central helixes that do remain parallels.
Second, the folding back of the region including the fusion peptide onto
a trimeric C-terminal region leads to the formation of a postfusion protein
structure with the outer regions zipped up against an inner trimeric core. Inter-
estingly, it has been described that all the class I, II, and III peptides can inhibit
this step by competing with the interaction of EnvGP-specific domain for the
formation of this structure.
et al
