Intermediate conformations during viral fusion glycoprotein structural transition

Abstract

Entry of enveloped viruses into cells requires the fusion of viral and cellular membranes, driven by conformational changes in viral glycoproteins. Three different classes of viral fusion proteins have been hitherto identified based on common structural elements. Crystal structures have provided static pictures of pre-fusion and post-fusion conformations of these proteins and have revealed the dramatic reorganization of the molecules, but the transition pathway remains elusive. In this review, we will focus on recent data aiming to characterize intermediate structures during the conformational change. All these data support the existence of a pre-hairpin intermediate, but its oligomeric status is still a matter of debate.

Figure 1

Ribbon illustrations of representative members of the three classes of viral fusion glycoproteins. Domains for the paramyxovirus (class I) and flavivirus (class II) proteins are colored and named according to [10, 11] and [12], respectively. Domains for the rhabdovirus (class III) protein are colored and named according to [21] with the exception that the central domain (CD) that was initially ascribed to two domains (DI and DII) is now considered as a single domain and corresponds to the previously described rigid block that remains invariant during the transition [21]. The dash lines represent the segments at the C-termini of the ectodomains that connect them to the TM domain (not represented). Respective pdb codes of each protein are showed in parentheses.

Figure 2

Models of viral fusion protein intermediates for class I (a) and class II (b) glycoproteins according to [29•, 34]. (a) In the case of paramyxovirus F glycoprotein, a trimeric pre-hairpin intermediate has been suggested to interact with the target membrane. This intermediate could be trapped by using a peptide derived from HRB (cyan cylinder), which inhibits fusion. It is believed that the interaction between the inhibitor and HRA (dark blue domain) mimics the six-helix bundle observed in the post-fusion state. (b) For class II fusion glycoproteins (here represented by E from Dengue virus), upon lowering the pH, the dimeric prefusion forms dissociates. Monomers interact with the target membrane and have been suggested to form trimeric pre-hairpin intermediates. In these intermediates, DIII have not folded back yet toward DI as in the E post-fusion form. The interaction of exogenous DIII with the trimeric intermediates prevents DIII foldback and blocks fusion. (c) Cartoon showing the complexity of the transition from the trimeric pre-hairpin intermediate to the trimeric post-fusion form. This transition requires a break of the threefold symmetry of the trimer (through bending of the molecule) together with a rotation of at least one of the C-terminal segments.

Figure 3

Plausible structural transition pathways of G at the viral surface. At pH 7.5, pre-fusion trimers and flexible monomers are in equilibrium at the viral surface. At pH 6.7, elongated monomeric structures are observed. Whether trimerization occurs after (pathway A) of before (pathway B) hairpin formation is not known for VSV G.