New study reveals the atomic interaction between the influenza M2–cholesterol complex

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When an influenza virus infects a host cell, it generates copies of itself in order to replicate. These viral copies then gather into viral buds that break free from the host cell in order to infect again.

It is known that the influenza M2 protein mediates this membrane scission through a cholesterol-dependent manner to cause budding and release. However, a recently published study in Proceedings of the National Academy of Sciences has revealed the precise atomic interaction that occurs during this process.

Researchers from Massachusetts’s Institute of Technology (MIT; MA, USA) used solid-state NMR spectroscopy to reveal that two cholesterol molecules bind to M2 in order to sever the viral buds from their host.

Within their study, they stated that: “This M2–cholesterol complex structure, together with previously observed M2 localization at phase boundaries, suggests that cholesterol mediates M2 clustering to the neck of the budding virus to cause the necessary curvature for membrane scission.”

This configuration – two cholesterol molecules attached to M2 – creates a wedge shape within the inner layer of the cell membrane. The wedge then produces a saddle-shaped curvature at the budding neck that is needed to sever the membrane and release the virus.

Previous research has demonstrated that the influenza M2 protein was necessary for viral budding and that this was dependent on cholesterol concentrations in the cell membrane; however, this new study demonstrates the exact role that cholesterol plays in releasing the virus.

The NMR technique employed in their research allowed Mei Hong (MIT) – a senior author of the study – and her colleagues to pin down cholesterol “in its natural environment in the membrane, where we also have the protein M2 in its natural environment,” Hong explained.

The researchers then measured the distance between cholesterol atoms and M2 protein atoms to determine how cholesterol molecules bind to M2, as well as to determine the orientation of cholesterol within the layers of the cell membrane.

Although the team’s research primarily focuses on the influenza M2 protein, they believe that this technique can be applied to an array of membrane proteins.

“About 30% 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 commented. “And now we have a tool for studying the cholesterol-binding structure of proteins.”

Hong concluded: “The new findings do not have any direct implications for vaccinating or treating flu, although they could inspire new research into how to prevent viral budding.”

Sources: Elkins MR, Williams JK, Gelenter MD et al. Cholesterol-binding site of the influenza M2 protein in lipid bilayers from solid-state NMR. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.1715127114 (2017) (Epub ahead of print); http://news.mit.edu/2017/cholesterol-helps-flu-virus-escape-through-host-cell-membrane-1120

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