Key mechanics of cell membrane fusion revealed
CHAPEL HILL - Scientists at the University of North Carolina School of Medicine in Chapel Hill have developed a new working model of cell membrane fusion.
The model, which apparently mimics the biochemical machinery of fusion in mammalian nerve membranes, offers researchers guidance for studying the biophysics of a process fundamental to all life.
In the future, knowledge gained from this research may also be applied to human disease control. It could help enhance development of fusion-blocking agents aimed at preventing infection by HIV, influenza, Ebola and other viruses. These viruses use membrane fusion machinery to enter cells. A report of the study appears in the April 10 issue of the journal Biochemistry. It details how a group of lipids, including cholesterol, can be combined in optimal ratios so that membrane fusion can occur experimentally.
Within living cells other than bacteria are compartments that carry out different functions such as protein production and processing. And those compartments are surrounded by a lipid bilayer membrane. Fusion allows movement from one compartment to another.
"The question of concern was how does the mix of lipids in a membrane make it more or less able to fuse with another membrane," said the study's lead author Barry R. Lentz, PhD, professor of biochemistry and biophysics at UNC.
Lentz, who heads UNC's Program in Molecular and Cellular Biophysics, and his collaborators approached the question by looking at a highly "fusagenic" membrane, one that's central to nervous system functioning: the synaptic vesicle membrane. Synaptic vesicles fuse with the surface membrane of the neuron, releasing neurotransmitters that bind to the adjacent neuron.
Lentz and his colleagues have developed a fusion model for that membrane based on liposomes, lipid sacs they produced in the laboratory from pure lipids. The researchers found that the addition of the polymer polyethylene glycol forced the liposomes close together and that they could then manipulate them to make them fuse. They had already discovered that fusion between these liposomes behaved in a remarkably similar fashion to fusion reported by other scientists between biological membranes.
By mixing several pure lipids in different proportions, Lentz and Md. Emdadul Haque, PhD, of UNC and Thomas J. McIntosh, PhD of Duke University Medical Center found they could optimize fusion with a mix of lipids (cholesterol, phosphatidylcholine, sphingomyelin, phosphatydilethanolamine and phosphatidylserine) basically in the same proportions found in natural synaptic vesicle membranes.
"What we found was really mind-blowing. The optimal mix that allows membranes to fuse to the greatest extent and rupture or lose their contents to the least extent was exactly the mix Nature has designed for the synaptic vesicle in mammalian cells. Very little is known about how lipid compositions affect fusion. This report offers the first insights into how Nature has optimized membranes for fusion and should help scientists better design liposomes for delivery of drugs into cells by fusion," Lentz said
"This is one more piece of evidence for what I see as the predominant hypothesis in the field now -- that fusion in a biological membrane is a process by which lipids undergo physical changes just like they undergo in the lab," Lentz noted.
But Lentz points out that lipids are not enough to drive fusion. The chemical machine that makes those changes occur also involve proteins. "And that's what we're studying now with our liposome model," he said.
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