A MECHANISM OF PROTEIN-MEDIATED FUSION - COUPLING BETWEEN REFOLDING OF THE INFLUENZA HEMAGGLUTININ AND LIPID REARRANGEMENTS

Although membrane fusion mediated by influenza virus hemagglutinin (HA ) is the best characterized example of ubiquitous protein-mediated fus ion, it is still not known how the low-pH-induced refolding of HA trim ers causes fusion. This refolding involves 1) repositioning of the hyd rophobic N-terminal sequence of the HA2 subunit of HA (''fusion peptid e''), and 2) the recruitment of additional residues to the cu-helical coiled coil of a rigid central rod of the trimer. We propose here a me chanism by which these conformational changes can cause local bending of the viral membrane, priming it for fusion. In this model fusion is triggered by incorporation of fusion peptides into viral membrane. Ref olding of a central rod exerts forces that pull the fusion peptides, t ending to bend the membrane around HA trimer into a saddle-like shape. Elastic energy drives self-assembly of these HA-containing membrane e lements in the plane of the membrane into a ring-like cluster. Bulging of the viral membrane within such cluster yields a dimple growing tow ard the bound target membrane. Bending stresses in the lipidic top of the dimple facilitate membrane fusion. We analyze the energetics of th is proposed sequence of membrane rearrangements, and demonstrate that this simple mechanism may explain some of the known phenomenological f eatures of fusion.