After a flu virus infects a host cell and hijacks its inner workings to create copies of itself, these copies gather into viral buds that break free from the host cell to infect again. A new study now provides the clearest picture yet of how the buds are pinched off from the host cell membrane.
Using a technique called solid-state nuclear magnetic resonance (NMR) spectroscopy, the team found that two cholesterol molecules bind to a flu protein called M2 to sever the viral buds from their host. The molecular configuration creates an exaggerated wedge shape inside the cell membrane that curves and narrows the neck of the budding virus until the neck breaks.
While previous research had demonstrated that M2's action during budding was dependent on cholesterol concentrations in the cell membrane, the new study demonstrates the exact role cholesterol plays in releasing the virus.
And although the team focused on a flu protein in their study, "we believe that with this approach we have developed, we can apply this technique to many membrane proteins," says senior author of the paper, which appears in the Proceedings of the National Academy of Sciences.
The amyloid precursor protein and alpha-synuclein, implicated in Alzheimer's disease and Parkinson's disease, respectively, are among the proteins that spend at least some of their lifetimes within cell membranes, which contain cholesterol in their fatty layers, the senior author says.
"About 30 percent of proteins encoded by the human genome are associated with the cell membrane, so you're talking about a lot of direct and indirect interactions with cholesterol," senior author notes. "And now we have a tool for studying the cholesterol-binding structure of proteins."
The NMR technique allowed the researchers to pin down cholesterol "in its natural environment in the membrane, where we also have the protein M2 in its natural environment," senior author says. The team was then able to measure the distance between cholesterol atoms and the atoms in the M2 protein to determine how cholesterol molecules bind to M2, as well as cholesterol's orientation within the layers of the cell membrane.
Cholesterol isn't evenly distributed throughout the cell membrane -- there are cholesterol-enriched "rafts" along with less enriched areas. The M2 protein tends to locate itself at the boundary between the raft and nonraft areas in the membrane, where the budding virus can enrich itself with cholesterol to build its viral envelope.
The observed configuration at the budding neck -- two cholesterol molecules attached to M2 -- creates a significant wedge shape within the inner layer of the cell membrane. The wedge produces a saddle-shaped curvature at the budding neck that is needed to sever the membrane and release the virus.
Cholesterol helps flu virus escape through host cell's membrane
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