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Scripps Research Structure of Virus Protein Reveals How Viruses Hijack Cell Proteins

New Finding May Help Scientists Understand How Some Viruses Cause Disease, Including Cancer

LA JOLLA, CA, July 31, 2009Viruses are masters at taking over a host cell’s machinery and using it to their own advantage. In doing so, they often disrupt the cell’s mechanisms for keeping cell growth and division in check, wreaking havoc.

In the July 27, 2009 issue of the Proceedings of the National Academy of Sciences (PNAS), researchers from The Scripps Research Institute describe for the first time the structure of a protein from a type of virus called adenovirus as it grabs hold of two cell proteins, preventing them from performing their normal jobs.

"By determining the structure, we understand at a molecular level how the virus interferes with cellular functions," says Scripps Research Professor Peter E. Wright, who is chair of the Department of Molecular Biology, Cecil H. and Ida M. Green Investigator in Biomedical Research, and member of the Skaggs Institute for Chemical Biology at Scripps Research.

Understanding how the adenovirus protein hijacks two cellular proteins for its own use should help scientists understand how similar proteins from related viruses, including the cancer-causing papillomavirus, cause disease, as well as direct the design of possible treatments.

Hijacked Proteins

Cells have tight regulatory mechanisms in place to limit their growth and division to appropriate times. That’s because uncontrolled cell growth can lead to cancer and other disorders.

Although adenovirus does not cause cancer in people, the virus can "transform" the cells it infects by disrupting their growth control mechanisms. Whereas human cells grown outside the body will divide a set number of times and then stop, cells infected with adenovirus will divide and grow indefinitely.

Researchers have long known that one protein from adenovirus, called E1A, is critical for this transformation. Thus, understanding how E1A functions would reveal how cell growth is regulated and how some viruses cause cancer.

One of the ways in which researchers determine a protein’s function is to look at the proteins it associates with.  E1A, for instance, interacts with two proteins that play important functions in controlling cell growth. The first, CPB, is a large protein that orchestrates the activities of hundreds of genes, turning them "on" at appropriate times. One of the genes whose activity is regulated by CBP is the gene that produces the anti-cancer protein p53. E1A also binds the retinoblastoma protein, pRb, another important anti-cancer protein.

So, how does E1A sabotage the functions of CBP and pRB? To answer the question Wright and colleagues decided to take a close-up look at the three proteins together.

Getting the Structure

To do so, they took advantage of a structural biology technique called nuclear magnetic resonance (NMR) spectroscopy.

With NMR, a magnetic field is applied to a sample that contains proteins or other molecules in a solution. That causes each nucleus in the molecule to resonate at a unique frequency that is then measured as a "peak" in a spectrum. By analyzing several NMR spectra, researchers can determine how a protein’s building blocks, or amino acids, are arranged in three-dimensional space.

But E1A proved to be a hard structure to crack. "E1A is a difficult protein. It aggregates easily, especially when it is in high concentrations, which is what you need for NMR," says Josephine C. Ferreon, a postdoctoral fellow in Wright’s lab.

To overcome the problem Ferreon and Wright started to examine segments of E1A small enough that they would not clump together, interfering with the NMR signal, but large enough that they would still bind to CBP and pRB. After testing different fragments and various conditions, they eventually hit on the right combination. "It took many tries to find the right area of E1A," explains Ferreon. "It was not an easy project. Had it been easy we would have had the structure many years ago."

From the time they found the first clear NMR signal, the researchers spent another year and a half gathering NMR data and analyzing it to produce a picture of the E1A protein bound to CBP and pRb.

Delivering a Double Whammy

This picture revealed that when E1A binds CBP it prevents the protein from binding to the cellular proteins it normally "talks" to. In particular CBP can no longer interact with the anti-cancer protein p53, shutting down p53’s functions.

In addition, when E1A binds to CBP and pRb simultaneously, it brings the two cellular proteins right next to one another. As a result, CBP "tags" pRb and pRb becomes degraded, shutting down all the cell functions they regulate.

"It is a double whammy," says Wright. "The E1A protein intervenes at two levels." By shutting down the functions of two anti-cancer proteins at once, E1A essentially takes the foot off the brake of cell growth.

The results, says Wright, were completely unexpected. Although researchers knew that E1A bound to CBP and pRb, no one knew how the binding occurred. "We did not know where CBP would bind or how close to pRb," says Wright. "Now we have a picture of how E1A works."

The knowledge, says Wright, will help researchers understand how another virus, the human papilloma virus, which can cause cancer of the cervix and other cancers, sabotages cellular functions. It might also help researchers design small molecules that can prevent E1A, and other related proteins, from grabbing hold of their cellular targets. "You could never get this information without the structure," says Wright.

In addition to Wright and Ferreon, co-authors of the study "Structural Basis for Subversion of Cellular Control Mechanisms by the Adenoviral E1A Oncoprotein" also include Maria Martinez-Yamout and H. Jane Dyson from Scripps Research. For more information, see http://www.pnas.org/content/early/2009/07/24/0906770106.abstract.

This research was supported by the National Institutes of Health, the Skaggs Institute for Chemical Biology, and a Leukemia and Lymphoma Society Special Fellowship.


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