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 New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>