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* The Laboratary of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, National
Institutes of Health, Bethesda Maryland 20892; and While the specificity and timing of membrane fusion in diverse physiological reactions, including virus-cell fusion, is determined by proteins, fusion
always involves the merger of membrane lipid bilayers.
We have isolated a lipid-dependent stage of cell-cell fusion mediated by influenza hemagglutinin and triggered by cell exposure to mildly acidic pH. This stage
preceded actual membrane merger and fusion pore formation but was subsequent to a low pH-induced change in hemagglutinin conformation that is required
for fusion. A low pH conformation of hemagglutinin
was required to achieve this lipid-dependent stage and
also, downstream of it, to drive fusion to completion.
The lower the pH of the medium applied to trigger fusion and, thus, the more hemagglutinin molecules activated, the less profound was the dependence of fusion
on lipids. Membrane-incorporated lipids affected fusion in a manner that correlated with their dynamic molecular shape, a characteristic that determines a lipid monolayer's propensity to bend in different directions.
The lipid sensitivity of this stage, i.e., inhibition of fusion by inverted cone-shaped lysophosphatidylcholine
and promotion by cone-shaped oleic acid, was consistent with the stalk hypothesis of fusion, suggesting that
fusion proteins begin membrane merger by promoting the formation of a bent, lipid-involving, stalk intermediate.
Laboratory of Bioelectrochemistry, Frumkin Institute of Electrochemistry,
Russian Academy of Sciences, Moscow, 117071 Russia
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