Abstract

The highly conserved N-terminal 23 residues of the HA2 subunit of the influenza glycoprotein hemagglutinin are often referred to as the fusion peptide, and it plays a pivotal role in fusing viral and host-cell membranes. At neutral pH, NMR reveals a tight helical-hairpin structure, stabilized by aliphatic hydrogen bonding and a charge-dipole interaction. At low pH, where the fusion process is triggered, the peptide transiently visits activated states which are likely to play a pivotal role in formation of the fusion pore, an essential structure required in the final stage of membrane fusion. Another critical step in membrane fusion involves the structural switch of the ecto-domain of class I viral fusion proteins from a prefusion state, to a post-fusion 6-helical bundle (6HB). A “spring-loaded” mechanism has been invoked to explain this structural transition and drive membrane fusion. Instead, we show that the transition involves disassembly of the ecto-domain through membrane binding, followed by assembly of 6HB on the membrane following fusion.