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 Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY

nachricht NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Future electronic components to be printed like newspapers

A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.

The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

A smart safe rechargeable zinc ion battery based on sol-gel transition electrolytes

20.07.2018 | Power and Electrical Engineering

Reversing cause and effect is no trouble for quantum computers

20.07.2018 | Information Technology

Princeton-UPenn research team finds physics treasure hidden in a wallpaper pattern

20.07.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>