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

doi:10.1083/jcb.140.6.1369

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© The Rockefeller University Press, 0021-9525/1998//1369 $5.00
The Journal of Cell Biology, Volume 140, Number 6, , 1998 1369-1382

Article

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 isunclear. We reversibly arrested hemagglutinin (HA)-mediatedcell–cell fusion right before fusion pore opening. A low-pHconformation of HA was required to form this intermediate andto ensure fusion beyond it. We present evidence indicatingthat outer monolayers of the fusing membranes were merged and continuous in this intermediate, but HA restricted lipid mixing.Depending on the surface density of HA and the membrane lipidcomposition, this restricted hemifusion intermediate eithertransformed into a fusion pore or expanded into an unrestrictedhemifusion, without pores but with unrestricted lipid mixing.Our results suggest that restriction of lipid flux by a ringof activated HA is necessary for successful fusion, during which a lipidic fusion pore develops in a local and transienthemifusion diaphragm.

Abbreviations used in this paper: CF, 6-carboxyfluorescein; FIF, frozen intermediate of fusion; GPI, glycosylphosphatidylinositol; GPI-HA, HA ectodomain linked to GPI; HA, influenza virus hemagglutinin; LPC, lysophosphatidylcholine; LPC-S, LPC-arrested fusion stage; NBD-taurine, N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) taurine; OA, oleic acid; R18, octadecyl rhodamine B; RBC, red blood cells.

Address all correspondence to Leonid V. Chernomordik, Building10, Room 10D04, 10 Center Drive, MSC 1855, Bethesda, MD 20892-1855. Tel.: (301) 594-1128. Fax: (301) 594-0813. E-mail: lchern{at}helix.nih.gov

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