Molecular Mechanisms of Flaviviral Membrane Fusion

Abstract

Enveloped viruses rely on transmembrane fusion proteins to fuse the viral membrane to the host-cell membrane and deliver the viral genome into the cytoplasm for replication. Although the structures and evolutionary origins of viral fusion proteins vary widely, all fusion proteins use the same physical principles and topology to drive membrane fusion. First, exposure of a hydrophobic fusion anchor allows them to insert into the host-cell membrane. Conserved hydrophobic residues in the fusion anchor penetrate part way into the outer bilayer leaflet of the host-cell membrane. The fusion protein then folds back on itself, directing the C-terminal viral transmembrane anchor toward the fusion loop. This fold-back forces the host-cell membrane (held by the fusion loop) and the viral membrane (held by the C-terminal transmembrane anchor) against one another until they fuse. In West Nile virus and other flaviviruses this fold-back in the fusion protein, E, is triggered by the reduced pH of an endosome, is accompanied by the assembly of E monomers into trimers, and occurs by domain rearrangement rather than by an extensive refolding of secondary structure. The rearrangement releases a large amount of energy, which is used to exert a bending force on the apposed viral and cellular membranes, propelling them toward each other and, eventually, causing them to fuse. The conserved regions of E that are responsible for driving membrane fusion are attractive targets for antiviral therapies.