Fig. 1.

Proposed mechanism of HA-mediated membrane fusion: (1) prefusion HA structure at pH 7 (PDB ID code 1HGF); (1 → 2) low endosomal pH triggers refolding of HA, swinging the binding domain HA₁ (red) away from HA₂; (2 → 3) B loop refolds, extending coiled-coil structure (green), exposing the fusion peptides (FPs) (dark blue) to the host membrane; path a forms fully extended coiled coil, maintaining threefold symmetry; path b partially extends coiled coil, forming a symmetry broken intermediate [Lin et al. (13)]; (3 → 4) foldback of S4, S5 to form antiparallel coiled coil, six-helix bundle scaffold and zipping of linker leashes, bringing FP and TMD together and host and viral membranes into apposition to promote fusion; (4 → 5) pore formation, possibly facilitated by interaction between TMD and FP; structure (5) is the postfusion structure of HA (PDB ID code 1QU1). (Inset) Prefusion structure of HA (1HGF) with color legend identifying HA₁ and each of the component structures of HA₂, including the FP, two β-strands (TBS), helix A (S1), B loop (S2), coiled coil (S3), hinge region (S4), and ectodomain and TMD (S5).