Structures of vesicular stomatitis virus glycoprotein: membrane fusion revisited

Abstract

Abstract. Glycoprotein G of the vesicular stomatitis virus (VSV) is involved in receptor recognition at the host cell surface and then, after endocytosis of the virion, triggers membrane fusion via a low pHinduced structural rearrangement. G is an atypical fusion protein, as there is a pH-dependent equilibrium between its pre-and post-fusion conformations. The atomic structures of these two conformations reveal that it is homologous to glycoprotein gB of herpesviruses and that it combines features of the previously characterized class I and class II fusion proteins.Comparison of the structures of G pre-and postfusion states shows a dramatic reorganization of the molecule that is reminiscent of that of paramyxovirus fusion protein F. It also allows identification of conserved key residues that constitute pH-sensitive molecular switches. Besides the similarities with other viral fusion machineries, the fusion properties and structures of G also reveal some striking particularities that invite us to reconsider a few dogmas concerning fusion proteins.

Features of a Spatially Constrained Cystine Loop in the p10 FAST Protein Ectodomain Define a New Class of Viral Fusion Peptides

“…An emerging hypothesis for the function of FPs in membrane fusion suggests that shallow insertion of amphipathic structures into the outer leaflet of bilayers induces high curvature stresses that are resolved by bilayer fusion (1,3,55). We note that the p10 HP is more amphiphilic than hydrophobic in nature, similar to the situation with the fusion loop of vesicular stomatitis virus G, which contains aromatic residues for membrane interaction but is much less hydrophobic than most FPs (50). Displacement of the hydrophobic residues from the apex of the p10 cystine loop may therefore reduce membrane insertion of the amphiphilic p10 HP and prevent induction of the membrane curvature needed to promote membrane fusion.…”

Acid-Activated Structural Reorganization of the Rift Valley Fever Virus Gc Fusion Protein

“…In general, viral fusion proteins convert to a stable form during fusion, thereby generating the energy needed for membrane coalescence. For class I and II viral fusion proteins, this transition was shown to be irreversible (51). Intriguingly, exposure of virus to the activating pH in the absence of target membranes also fully converts Gc into the stable oligomer; however, although a reduction is seen, it does not completely inactivate virus infectivity even after incubation times of up to 16 min (data not shown).…”

Enhanced pseudotyping efficiency of HIV-1 lentiviral vectors by a rabies/vesicular stomatitis virus chimeric envelope glycoprotein

“…The VSVG protein sequence shows low but significant sequence homology with RVG 25 and is thought to share several structural and functional properties with RVG. The structure of the VSVG extracellular domain reviewed in Roche et al 26 has been determined both in its prefusion 24 and low pH 23 forms by X-ray crystallography after proteolytic treatment to remove disordered regions. Based on these observations we defined the extracellular portion of both VSVG and RVG as consisting of the receptor-binding domain (also mediating membrane fusion) and a less ordered stalk domain (see Figure 2b) linking it to the hydrophobic transmembrane domain as defined in Rose et al 27 Using the PCR and splicing by overlap extension (SOE), 28 envelope protein expression plasmids were generated encoding RVG/VSVG chimeric proteins in which: (1) the cytoplasmic domain of RVG was replaced with the cytoplasmic domain of VSVG (RVG/VSVG(C)), (2) the cytoplasmic and transmembrane domains of RVG were replaced by the cytoplasmic and transmembrane domains of VSVG (RVG/VSVG(TC)) and (3) the cytoplasmic and transmembrane domains and most of the extracellular stalk domain of RVG were replaced by the corresponding region of VSVG (RVG/VSVG(STC)).…”