CHAPEL HILL – Scientists at the University of North Carolina School
of Medicine in Chapel Hill have developed a new working model of cell
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
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.