Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers uncover clues to flu’s mechanisms

01.08.2014

Rice, Baylor scientists analyze how influenza-related proteins help infect cells

A flu virus acts like a Trojan horse as it attacks and infects host cells. Scientists at Rice University and Baylor College of Medicine have acquired a clearer view of the well-hidden mechanism involved.


The influenza hemagglutinin protein reconfigures itself as it targets host cells to infect them. Until new analysis by Rice University and Baylor College of Medicine researchers, nobody had been able to study the intermediate states of the protein-refolding process that may be vulnerable to treatment with drugs. (Credit: Jeffrey Noel/Rice University)

Their computer simulations may lead to new strategies to stop influenza, perhaps even a one-size-fits-all vaccine. The discovery detailed this week in the Proceedings of the National Academy of Sciences shows the path taken by hemagglutinin, a glycoprotein that rides the surface of the influenza virus, as it releases fusion peptides to invade a host cell.

The release mechanism has been the subject of many theories, but none have explained experimental observations as well as the new work led by biophysicist José Onuchic at Rice and biochemists Qinghua Wang at Baylor and Jianpeng Ma, who has a joint appointment at the two institutions. The Rice-Baylor team applied protein-folding algorithms developed by Onuchic and his colleagues to analyze how hemagglutinin reconfigures itself as it infects a cell.

... more about:
»NSF »Physics »X-ray »energy »flu »landscape »mechanisms »protein »structures

Hemagglutinin is completely folded at the start of the process of interest to researchers who study viral infection, Ma said. “It may be the only case known to human beings where a protein starts at a fixed point and literally completely refolds,” he said. Proteins are the molecular motors that spring from DNA and perform tasks essential to life, and they are the prime focus of study for Onuchic and his colleagues at Rice’s Center for Theoretical Biological Physics (CTBP). The researchers use their energy landscape theory to determine the path an unfolded strand of amino acids takes as it collapses into a final, functional protein.

That involves calculating the energetic preferences of every acid in the chain as well as the influence of the surrounding environment as folding progresses. When Ma met Onuchic a few years ago, he recognized an opportunity. “I told him there’s a very important feature of the viral system that would be ideal for his energy landscape approach.” Ma said. Researchers have long observed hemagglutinin’s initial and final structures through X-ray crystallography. But because the change happens so quickly, it has been impossible to capture an image of the glycoprotein in transit.

Ma said the key to stopping the flu could be to attack these intermediate structures. Energy landscape theory predicts how a protein will fold no matter how fast it happens. In the case of hemagglutinin, the unfolding and refolding happens in seconds. During the process, part of the protein “cracks” and releases fusion peptides. “The fusion peptides are the most important part of the molecule,” said Rice postdoctoral researcher and co-author Jeffrey Noel. “The hemagglutinin is attached to the viral membrane, and when these peptides are released, they embed themselves in the target cell’s membrane, creating a connection between the two.”

“The purpose of hemagglutinin is to poke a hole between the two membranes,” Ma said. “They have to fuse so the genetic material will be injected into the human cell.” Hemagglutinin is recognized by polysaccharide receptors on host cells and is absorbed when the cells engulf it. Initially, part of the protein forms a cap that protects the segments inside. Acidic conditions cause the cap to fall off, and the protein begins to reconfigure itself. “The release of the fusion peptide, which is initially hidden inside hemagglutinin, is triggered by that giant conformational change,” Ma said. “When the cap is on, the whole protein is stable,” Noel said.

“What we see in the simulation is that the hydrophobic pocket where the fusion peptides are buried is very unstable and wants to crack as soon as the cap comes off.” By using the experimental structural information from X-ray crystallography to approximate the full energy landscape of hemagglutinin, the researchers can now capture a rough picture of the steps involved in its reconfiguration, including the point at which the peptides are released. “We now, for the first time, have mapped out the entire process, going from state A to state B, and the energetics along the way,” Ma said.

Ma said frequent mutations to the cap help the virus avoid antibodies; this is the reason people need flu shots every year. But he suspects the inner part of the protein is more highly conserved. “We’re targeting the part that the virus cannot afford to change. Therefore, it provides more hope for developing therapeutic agents,” he said. Such agents could lead to a universal flu vaccine that would last a lifetime. He said the membrane fusion mechanism is widely shared among many biological systems, which makes influenza a good model for studying other diseases.

“HIV has one. Ebola has one. And it’s also shared by intercell transport in the nervous system,” Ma said. He noted the work could not have been done without CTBP, which moved to Rice from the University of California, San Diego, three years ago to take advantage of collaborations with Texas Medical Center researchers – one of Rice’s Priorities for the New Century.

“This demonstrates a very interesting collaboration between TMC and Rice,” Ma said. “We’re very happy with that.” The paper’s co-authors are Rice graduate students Xingcheng Lin and Nathanial Eddy, and Paul Whitford, an assistant professor at Northeastern University in Boston. Onuchic is Rice’s Harry C. and Olga K. Wiess Professor of Physics and Astronomy and co-director of the CTBP based at Rice’s BioScience Research Collaborative.

Ma is a professor of bioengineering at Rice and the Lodwick T. Bolin Professor of Biochemistry at Baylor. Wang is an assistant professor of biochemistry and molecular biology at Baylor. The National Science Foundation (NSF), the Welch Foundation, the National Institutes of Health, the Gillson-Longenbaugh Foundation and the Cancer Prevention Research Institute of Texas supported the research. The researchers utilized the Data Analysis and Visualization Cyberinfrastructure (DAVinCI) supercomputer supported by the NSF and the BlueBioU supercomputer, both administered by Rice’s Ken Kennedy Institute for Information Technology.

Jeff Falk | Eurek Alert!
Further information:
http://news.rice.edu/2014/07/31/researchers-uncover-clues-to-flus-mechanisms/

Further reports about: NSF Physics X-ray energy flu landscape mechanisms protein structures

More articles from Life Sciences:

nachricht Bare bones: Making bones transparent
27.04.2017 | California Institute of Technology

nachricht Link Discovered between Immune System, Brain Structure and Memory
26.04.2017 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

Bare bones: Making bones transparent

27.04.2017 | Life Sciences

Study offers new theoretical approach to describing non-equilibrium phase transitions

27.04.2017 | Physics and Astronomy

From volcano's slope, NASA instrument looks sky high and to the future

27.04.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>