The Pathway of Membrane Fusion Catalyzed by Influenza Hemagglutinin: Restriction of Lipids, Hemifusion, and Lipidic Fusion Pore Formation

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J. Cell Biol., Volume 140, Number 6, March 23, 1998 1369-1382

The Pathway of Membrane Fusion Catalyzed by Influenza Hemagglutinin: Restriction of Lipids, Hemifusion, and Lipidic Fusion Pore Formation

Leonid V. Chernomordik,^* Vadim A. Frolov, Eugenia Leikina,^* Peter Bronk,^* and Joshua Zimmerberg^*

^* Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1855; and Laboratory of Bioelectrochemistry, A.N. Frumkin Institute of Electrochemistry, Russian Academy of Science, Moscow, 117071, Russia

The mechanism of bilayer unification in biological fusion is unclear. We reversibly arrested hemagglutinin (HA)-mediated cell-cellfusion right before fusion pore opening. A low-pH conformationof HA was required to form this intermediate and to ensure fusionbeyond it. We present evidence indicating that outer monolayersof the fusing membranes were merged and continuous in this intermediate,but HA restricted lipid mixing. Depending on the surface densityof HA and the membrane lipid composition, this restricted hemifusionintermediate either transformed into a fusion pore or expandedinto an unrestricted hemifusion, without pores but with unrestrictedlipid mixing. Our results suggest that restriction of lipid fluxby a ring of activated HA is necessary for successful fusion,during which a lipidic fusion pore develops in a local and transienthemifusion diaphragm.

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