One flu over: NMR insights

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  • Published: Dec 15, 2017
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: One flu over: NMR insights

Under the influenza

When you catch influenza, the virus hijacks the inner workings of your cells to make copies of itself. The copies accumulate in viral buds that then break free from the host cell to infect another host. Researchers at Massachusetts Institute of Technology have now used solid-state nuclear magnetic resonance (NMR) spectroscopy to obtain a clear picture of how these buds pinch off from the host cell membrane.

When you catch influenza, the virus hijacks the inner workings of your cells to make copies of itself. The copies accumulate in viral buds that then break free from the host cell to infect another host. Researchers at Massachusetts Institute of Technology have now used solid-state nuclear magnetic resonance (NMR) spectroscopy to obtain a clear picture of how these buds pinch off from the host cell membrane in the case of influenza H3N2.

Matthew Elkins, Jonathan Williams, Martin Gelenter, Peng Dai, Byungsu Kwon, Ivan Sergeyev, Bradley Pentelute, and Mei Hong found that two cholesterol molecules bind to the influenza protein M2 to cleave the viral buds from their host cell membrane. This molecular configuration forms an exaggerated wedge shape within the membrane that curves and narrows the neck of the budding virus until the neck breaks. Earlier work had already shown that the activity of M2 during budding is dependent on the concentration of cholesterol in the cell membrane but the new study reported in the Proceedings of the National Academy of Sciences shows its precise role in freeing the new viruses to infect other cells in the body and other people.

The influenza virus protein M2 is essential to the process of viral budding. Viral budding itself occurs most effectively in cell membranes with a particular concentration of cholesterol. Hong and her colleagues were curious, however, as to why this should be the case. Indeed, they wanted to know whether M2 directly interacts with cholesterol molecules or not. That was where their solid-state NMR expertise came into its own.

Cholesterol in context

In this context studying cholesterol and its dynamic interactions with many different proteins within the cell membrane was complicated. The interactions are myriad and the environment, the cell membrane, is itself dynamic and disordered, which complicates matters still further. Hong and her colleagues were able to home in on cholesterol "in its natural environment in the membrane, where we also have the protein M2," she explains. The team could then 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. The team points out that cholesterol is not evenly distributed within the cell membrane. Instead, there are cholesterol-rich "rafts" along with less enriched areas. The viral M2 protein tends to locate itself at the boundary between these raft and non-raft regions, so that the budding virus can enrich itself with cholesterol to build its viral envelope.

Deeper understanding

At the moment, there are no immediate medical implications for the work, it will most likely not lead to a new type of treatment nor a vaccine. However, it might inspire other research into how to prevent viral budding. Moreover, Hong adds that even though the researchers focused on a single flu protein, the same approach they have developed could be used to study the behaviour of many other membrane proteins. Given that membrane proteins are notoriously difficult to crystallize and are thus essentially off-limits to X-ray crystallographic techniques, this work shows once again the prowess of solid state NMR spectroscopy for this kind of protein. Other proteins that exist in the membrane for at least some of the time include amyloid precursor protein and alpha-synuclein, which are implicated in Alzheimer's disease and Parkinson's disease, respectively.

"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," Hong explains. "And now we have a tool for studying the cholesterol-binding structure of proteins," she says.

Related Links

Proc Natl Acad Sci 2017, 114, 12946-12951: "Cholesterol-binding site of the influenza M2 protein in lipid bilayers from solid-state NMR"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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