Sep. 26, 2001 UPTON, NY -- As part of an ongoing effort to understand how viruses infect cells, scientists at the U.S. Department of Energy's Brookhaven National Laboratory have deciphered the molecular-level interaction between coxsackievirus -- which infects the heart, brain, pancreas, and other organs -- and the human cell protein to which it attaches.
This work, published in the October issue of Nature Structural Biology, may lead to improved ways to thwart viral infections, and may help scientists design virus-based vehicles for gene therapy.
The study reveals that the receptor protein for coxsackievirus (known as coxsackievirus-adenovirus receptor, or CAR) forms pairs on the surface of human cells, with two adjacent CAR receptors attached to one another below the surface of the cell membrane. When coxsackievirus binds to the human cell, it forms bonds with both receptors of the pair.
"This arrangement is advantageous for the virus," says Brookhaven biologist Paul Freimuth, one of the study's authors. "The binding becomes almost irreversible, because both bonds would have to reverse simultaneously to release the virus. That increases the likelihood that the virus will infect the cell."
The structural studies also reveal that the binding sites on the coxsackievirus are "cleverly" hidden from the body's immune system, which produces antibodies to fight infections. "If you think of the virus as a golf ball, the binding sites that recognize the receptor are inside the dimples," Freimuth says. "Antibodies can't fit into the indentations, but the receptor is a slender molecule that can fit in."
Both of these features -- hidden binding sites and simultaneous binding to multiple receptors -- are shared by other viruses in the same family, including the virus that causes polio and rhinovirus, one cause of the common cold and other respiratory and gastrointestinal infections.
"It's a very clever arrangement that these viruses have worked out," Freimuth says, "and very hard to defeat." For example, scientists have tried administering single receptor-like molecules designed to tie up binding sites on a virus and block its ability to attach to cells. These haven't worked very well, Freimuth suggests, because the double hold the virus forms with the cell makes it hard for these single molecules to compete. But perhaps administering receptor-like molecules with double binding sites would be able to compete and interfere with the virus' attack.
The current work may also help scientists interested in developing viruses used in gene therapy. The idea behind gene therapy is to destroy a virus’ disease-causing genes and replace them with therapeutic genes -- ones that might fix a genetic defect that causes cancer or some other disease.
Being able to tailor-make viruses that bind to specific receptors could help deliver the genes to cells where they are needed without affecting other cells. And the knowledge that multiple binding sites help viruses gain a strong hold could help scientists to make these designer viruses more effective delivery vehicles. Tailor-made viruses may also offer insight into studies of systems biology -- for example, how added genes affect behavior see: http://www.bnl.gov/bnlweb/pubaf/pr/bnlpr090501.htm.
The structural details reported in the current study were derived by cryo-electron microscopy -- the analysis of frozen samples of the virus bound to partial and full receptor molecules. This part of the study was performed at Purdue University. Cloning and sequencing the receptor gene and producing the receptor protein were all performed at Brookhaven Lab.
The data were also correlated with a previous study of a portion of the CAR protein bound to adenovirus, performed at Brookhaven’s National Synchrotron Light Source and published by Freimuth and others in 1999 see: http://www.bnl.gov/bnlweb/pubaf/pr/bnlpr111899.html.
Brookhaven Lab just received $750 thousand from the U.S. Department of Energy to purchase its own cryo-electron microscope, so that this kind of complementary approach to the study of biological molecules can now take place entirely at the Lab.
This research was funded by the National Institutes of Health, the Keck Foundation, Purdue University, and the U.S. Department of Energy, which supports basic research in a variety of scientific fields.
The U.S. Department of Energy's Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies. Brookhaven also builds and operates major facilities available to university, industrial, and government scientists.
The Laboratory is managed by Brookhaven Science Associates, a limited liability company founded by Stony Brook University and Battelle, a nonprofit applied science and technology organization.
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