Nav: Home

Cholesterol helps flu virus escape through host cell's membrane

November 20, 2017

CAMBRIDGE, MA -- 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 from MIT 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 MIT 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 Mei Hong, an MIT professor of chemistry and senior author of the paper, which appears in the Proceedings of the National Academy of Sciences the week of Nov. 20.

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

Dynamic challenges

Earlier imaging and experimental studies showed that flu's M2 protein was necessary for viral budding, and that the budding worked best in cell membranes containing a specific concentration of cholesterol. "But we were curious," Hong says, "about whether cholesterol molecules actually bind or interact with M2. This is where our expertise with solid-state NMR comes in."

NMR uses the magnetic properties of atomic nuclei to reveal the structures of the molecules containing those nuclei. The technique is especially well-suited to studying cholesterol, "which has been generally difficult to measure on a molecular level because it's just so small and dynamic, interacting with many proteins, and the cell membrane where we observe it is also dynamic and disordered," Hong says.

The NMR technique allowed Hong 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," she 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 and membrane curvature

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 configuration that Hong and her colleagues observed 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.

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, Hong says.
-end-
The research was funded by the National Institutes of Health.

Massachusetts Institute of Technology

Related Cholesterol Articles:

Cholesterol's effects on cellular membranes
The findings have far-reaching implications in the general understanding of disease, the design of drug delivery methods, and many other biological applications that require specific assumptions about the role of cholesterol in cell membranes.
Autism-cholesterol link
Study identifies genetic link between cholesterol alterations and autism.
Microbes might manage your cholesterol
Researchers discover a link between human blood cholesterol levels and a gene in the microbiome that could one day help people manage their cholesterol through diet, probiotics, or entirely new types of treatment.
Experimental cholesterol-lowering drug effective at lowering bad cholesterol, study shows
Twice-yearly injections of an experimental cholesterol-lowering drug, inclisiran, were effective at reducing low-density lipoprotein (LDL) cholesterol, often called bad cholesterol, in patients already taking the maximum dose of statin drugs, according to data of the ORION-10 trial presented Saturday, Nov.
Rethinking how cholesterol is integrated into cells
Cholesterol is best known in connection with cardiovascular disease, but cholesterol is also vital for many fundamental processes in the body.
Seed oils are best for LDL cholesterol
Using a statistical technique called network meta-analysis, researchers have combined the results of dozens of studies of dietary oils to identify those with the best effect on patients' LDL cholesterol and other blood lipids.
Cholesterol leash: Key tethering protein found to transport cellular cholesterol
Cholesterol is an essential component of living organisms, but the mechanisms that transport cholesterol inside the cell are poorly understood.
New way to treat cholesterol may be on the horizon
A breakthrough discovery by scientists at Houston Methodist Research Institute could change the way we treat cholesterol.
How low should LDL cholesterol go?
New analysis shows that in a high-risk population, achieving ultra-low LDL cholesterol levels, down to <10 mg/dL, safely results in additional lowering of risk of cardiovascular events.
Does boosting 'good' cholesterol really improve your health?
A new review addresses the mysteries behind 'good' HDL cholesterol and why boosting its levels does not necessarily provide protection from cardiovascular risk for patients.
More Cholesterol News and Cholesterol Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.