Single-Molecule Analysis of a Viral Fusion Protein Illuminates a Fusion-Active Intermediate State

The influenza virus hemagglutinin (HA) fusion glycoprotein mediates viral entry into host cells through its receptor binding and membrane fusion activities. In this issue of Cell, Das et al. use single-molecule Förster resonance energy transfer (smFRET) to monitor HA conformational dynamics. Their study reveals this prototypical class I fusion protein to be a highly dynamic molecule capable of reversibly sampling multiple states, including on-pathway fusion intermediates between pre-fusion and post-fusion endpoints. These findings challenge long-held ideas for how HA functions and move the field closer to obtaining a mechanistic understanding of how class I fusion proteins mediate membrane fusion.