Rice, Baylor scientists analyze how proteins help from the flu infect cells -
A influenza virus acts like a Trojan horse because it attacks and infects cells hosts. Scientists at Rice University and Baylor College of Medicine have developed a clearer picture of the hidden mechanism involved.
Their computer simulations may lead to new strategies to stop the flu, maybe even a one-size-fits-all vaccine.
detailed the discovery this week in the Proceedings of the National Academy of Sciences shows the path the hemagglutinin glycoprotein that overlaps the surface of the influenza virus, because it releases the fusion peptides to invade a host cell.
the release mechanism has been many theories, but none have explained the experimental observations and the new work of biophysicist Jos- Onuchic and biochemists at Rice Qinghua Wang at Baylor and My Jianpeng who has a joint appointment at the two institutions.
The Rice-Baylor team applied protein folding algorithms developed by Onuchic and colleagues to analyze how the hemagglutinin reconfigures as it infects a cell.
hemagglutinin is completely folded early in the process of interest to researchers studying viral infection, Ma said. "It may be the only known case of humans, a protein which begins at a fixed point and literally collapses completely," he said.
Proteins are the molecular motors Spring DNA and perform tasks essential to life, and they are the main object of study for Onuchic and colleagues at Rice Centre biological theoretical physics (CTBP). Researchers use their energy landscape theory to determine the path of a folded strand of amino acids takes as he collapses in a final protein functional. This involves calculating energy preferences of each acid in the chain, and the influence of the environment that the folding progresses.
When Ma met Onuchic few years ago, he recognized the opportunity. "I told him that there is a very important element of the viral system that would be ideal for his approach to the energy landscape." Ma said.
Researchers have long observed the initial and final structures of hemagglutinin by X-ray crystallography But because change happens so quickly, it was impossible to capture an image of the glycoprotein in transit. Ma said the key to stopping the flu could be attacking these intermediate structures.
energy theory predicts landscape of how a protein folds no matter how fast it happens. In the case of HA, the unfolding and folding occurs in seconds. In the process, part of the "cracks" protein and fusion peptides releases.
"The fusion peptides are the most important part of the molecule," said Rice postdoctoral researcher and co-author Jeffrey Christmas. "The hemagglutinin is committed to the viral membrane, and when these peptides are released, they drown in the membrane of the target cell, creating a link between the two."
"The purpose of hemagglutinin is to drill a hole between the two membranes," said Ma. "They need to melt so that the genetic material is injected into the human cell."
is recognized by hemagglutinin receptors on host cells polysaccharides and is absorbed when cells engulf. initially, a portion of the protein forms a cap which protects the segments inside.
the acidic conditions cause the cap to fall, and the protein begins to reconfigure themselves. "the release of the fusion peptide, which is initially hidden inside hemagglutinin, is triggered by this conformational change giant," said Ma.
"When the cap is on, the whole protein is stable," said Noel. "What we see in the simulation is that the hydrophobic pocket where the fusion peptides are buried is very unstable and will break when the cap comes off."
Using the experimental structural information from X-ray crystallography to bring the entire energy landscape hemagglutinin, researchers can now capture a rough picture of the stages of its reconfiguration, including the point at which the peptides are released. "We now, for the first time, have the entire route of the process from the state A to state B, and energetics along the way," said Ma.
Ma said frequent mutations with the antibodies prevent viruses cap;. this is the reason people need vaccines against influenza every year, but he suspects the inner part of the protein is highly conserved "We aim the part. the virus can not afford to change. therefore, it offers no hope for the development of therapeutic agents, "he said. These agents could lead to a vaccine against pandemic influenza that would last a lifetime.
He stated that the membrane fusion mechanism is widely shared by many biological systems, which makes the flu a good model for studying other diseases. "HIV is one. Ebola has a. And it is also shared by intercellular transmission in the nervous system, "said Ma.
He noted the work could not be done without CTBP, who moved to Rice University of California San Diego, there are three years to take advantage of collaborations with researchers at the Texas Medical Center. - one of the priorities of rice for the new century "This demonstrates a very interesting collaboration between TMC and rice," said Ma ". We are very happy."
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