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    • PHA-793887 Indeed it was shown further in

    2021-10-19

    Indeed, it was shown further in VSV G that the H80A mutation, and the E123L and D121L double mutation, which both abolish VSV G fusion properties, were rescued by the same compensatory Q112P mutation. In a single FD, residue 112 is located on the opposite side of the three-stranded β-sheet and is far from residues 121 and 123 (Fig. 2d). However, in the CHAV Gth crystal structure, H80, E112, D121and E123 are clustered on the same side of the intermolecular β-sheet [31] (Fig. 2c). This strongly suggests that the antiparallel association of the FDs observed in the crystal of CHAV Gth is functionally relevant and crucial for fusion.
    Toward a model for vesiculovirus membrane fusion Using an in vitro system to characterize fusion between VSV virions and liposomes, it has been demonstrated that the glycoproteins play two distinct roles (Fig. 3). First, in the contact zone with the target membrane, they drive the formation of the initial fusion pore (Fig. 3b and c). The flat PHA-793887 of the bullet-shaped virions is the favored site for this process [38]. We suggest that flat assemblies involving antiparallel interactions between the FD β-sheet, similar to those described in the previous paragraph, are involved at this stage. Such an assembly, by exposing the fusion loops, is ideally suited to constitute the first bridge between the target membrane and the flat base of the viral particle (Fig. 3b). Several features should favor the formation of such intermediates specifically at the flat base of the virus, including the difference in membrane curvature (which is zero at the viral base), the lower density of viral glycoproteins [38] and maybe also distinct interactions with intraviral matrix proteins which may control G oligomeric status. Whether several such dimer-based assemblies cooperate to initiate the fusion process remains an open question. In addition, the fate of those oligomers at later stages of the fusion process is unknown. The second stage is pore enlargement (Fig. 3d), which is the most energetically expensive step [44]. It has been shown that the spikes located outside the contact zone play a decisive role in this ultimate step by forming a helical network of post-fusion trimers [38]. Here, the structural transition toward the post-fusion trimer proceeds through monomeric EI and LI conformations (Fig. 3). It is worth noting that, using native mass spectrometry, dimeric assemblies of both VSV G and CHAV G have been detected at pH 7.5 [31]. At such a pH, post-fusion trimers are not yet formed. Together with the progressive pH decrease after virion endocytosis, this might allow a for temporal regulation of the formation of the different oligomeric species.
    Differences and similarities with other viral fusion glycoproteins We are aware that our structural data challenge the current model proposed for both class I and class II fusion glycoproteins [16], and sometimes for class III glycoproteins [26], [27]. The current model postulates the formation of the so-called trimeric elongated pre-hairpin conformation that bridges the viral and target membranes. For class I [45], [46], [47], [48] and class II [49], [50], [51], several experimental data are consistent with this model. However, the pathway of the structural transition that we propose for vesiculovirus G does not go through such a trimeric elongated pre-hairpin conformation, which has never been observed at the viral surface. The question, which then arises, is whether the working of the vesiculovirus machinery is different from that of other viruses. This is all the more pertinent because (i) all the experimental data suggest that the membrane fusion pathway (i.e., the lipidic intermediates which are formed) is very similar for all the enveloped viruses studied so far regardless of the organization of their fusion machinery [52], [53], [54], and (ii) fusion kinetics of individual virions for influenza virus (class I), West Nile virus (class II), and VSV could all be fit to models based on very similar sequence of conformational events [13], [55], [56]. Therefore, in this last part, we will discuss data obtained on other viral fusion glycoproteins from both class I and class II and focus on some features reminiscent of what is observed for vesiculovirus G.