Figure 3. Influenza virus hemagglutinin: proposed sequence of fusogenic conformational changes.

(a) The pre-fusion conformation. Each subunit is shown in a different color. The binding site for the receptor, sialic acid, is at the top of each subunit, but contact with a receptor molecule is not shown. Red asterisk, the sequestered fusion peptide of the red subunit, at the N terminus of HA2. (b) HA1 dissociates from its tightly docked position in response to proton binding. Each HA1 remains flexibly tethered to the corresponding HA2 by a disulfide bond (near the bottom of the ectodomain, in the orientation shown here). (c) The extended intermediate. The loop between the shorter and longer helices in HA2 (for example, the two red helices and the loop connecting them, in b) becomes a helix, thereby translocating the fusion peptide toward the target membrane. The fusion peptides (asterisk) are shown interacting as amphipathic helices with the target bilayer. The loop-to-helix transition creates a long, three-chain coiled coil at the core of the trimer. (d) Collapse of the extended intermediate to generate the post-fusion conformation. The lower parts of the protein (as seen in the orientation in c) fold back along the outside of the three-chain coiled coil. The collapse is complete only when the two membranes have fused completely. The post-fusion conformation is shown in a 'horizontal' orientation, to correspond to the sequence in Figure 1. (e) Detail illustrating some features of the membrane-proximal region of influenza virus HA2 after fusion is complete. The N termini of the coiled-coil helices are capped by contacts with amino acid residues in the link between the fusion peptide and the coiled coil, as well as with residues near the C terminus of the ectodomain, proximal to the transmembrane helices²⁴. This cap locks into place all the membrane-proximal components of the structure. The fusion peptides at the N termini of three HA2 chains are shown as cylinders (possible amphipathic helices) lying partly immersed in the outer leaflet of the membrane bilayer, as suggested by NMR and EPR studies²⁷. The transmembrane segments, likely to be α-helices, are also shown as cylinders. The relationships in this drawing among the fusion peptides and the transmembrane helices, chosen to illustrate the scale of the structures and the approximate distances between them, are purely schematic, as there is no single structure yet determined experimentally that contains all the elements included here. Only the crystallographically determined components are in ribbon representation.