Membrane structure and fusion-triggering conformational change of the fusion domain from influenza hemagglutinin

The N-terminal domain of the influenza hemagglutinin (HA) is the only porti on of the molecule that inserts deeply into membranes of infected cells to mediate the viral and the host cell membrane fusion. This domain constitute s an autonomous folding unit in the membrane, causes hemolysis of red blood cells and catalyzes lipid exchange between juxtaposed membranes in a pH-de pendent manner. Combining NMR structures determined at pHs 7.4 and 5 with E PR distance constraints, we have deduced the structures of the N-terminal d omain of HA in the lipid bilayer. At both pHs, the domain is a kinked, pred ominantly helical amphipathic structure. At the fusogenic pH 5, however, th e domain has a sharper bend, an additional 3(10)-helix and a twist, resulti ng in the repositioning of Glu 15 and Asp 19 relative to that at the nonfus ogenic pH 7.4. Rotation of these charged residues out of the membrane plane creates a hydrophobic pocket that allows a deeper insertion of the fusion domain into the core of the lipid bilayer. Such an insertion mode could per turb lipid packing and facilitate lipid mixing between juxtaposed membranes .