FUSION PORE DYNAMICS IN INFLUENZA HEMAGGLUTININ-MEDIATED MEMBRANE FUSION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. We initiated a theoretical study of fusion pore dynamics in influenza hemagglutinin-mediated membrane fusion using shell theory (a branch of continuum mechanics). Currently the most popular model for membrane fusion is the stalk model, or hemifusion hypothesis (1). It proposed that membrane fusion starts with formation of an intermediate membrane structure, in which the outer leaflets of the two interacting membranes are fused, forming a stalk; while the inner leaflets are intimately apposed, forming a diaphragm. A lateral expansion of the stalk opens a fusion pore in the diaphragm. Enlargement of the fusion pore will lead to complete membrane fusion. However, it has been found that significant vesicle (cell) content leaking occurs during HA-mediated membrane fusion (2). The content leaking was shown to be correlated with fusion pore flickering (open and close repeatedly) (3). These observations contradict a non-leaking fusion event implied by the stalk model. We have used shell theory to work out mechanisms for initial opening of fusion pore, pore flickering, and pore enlargement for both vesicle and viral membranes in vesicle-influenza virus fusion. We suggest a relation between the fusion pore dynamics with the reported content leakage during influenza hemagglutinin-mediated membrane fusion. (1) Chernomordik, L.V., M. Kozlov. 2005. Membrane hemifusion: crossing a chasm in two leaps. Cell. 123:375-382. (2) Bonnafous, P., and T. Stegmann. 2000. Membrane perturbation and fusion pore formation in influenza hemagglutinin-mediated membrane fusion. J. Biol. Chem. 275:6160-6166. (3) Frolov, V.A., A.Y. Dunina-Barkovskaya, A.V. Samsonov, and J. Zimmerberg. 2003. Membrane permeability changes at early stages of influenza hemagglutinin-mediated fusion. Biophys, J, 85:1725-1733.