X-rays Reveal Details Of Cancer Protein

The series of high-resolution “snapshots” of the tumor-causing protein may lead to new insights into how viruses cause cancers, said Xiaojiang Chen, an associate professor of biological sciences in the USC College of Letters, Arts and Sciences.

The protein, called “large T” antigen, comes from the SV40 virus, which causes tumors in monkeys. In the lab, the viral protein can transform healthy cells into cancerous ones.

But scientists have long been puzzled about how the large T accomplishes this and other key functions.

Working with the cell’s own proteins, large T turns into a “molecular machine” that transforms the energy from the cellular fuel molecule ATP into mechanical work.

Reporting in the Oct. 1 issue of the journal Cell, Chen and his team offered the first play-by-play, atomic-level images of the protein as it unzips and unwinds the double helix of DNA so that genetic material can be copied.

“The saying goes, ‘A picture is worth a thousand words.’ In this case, it’s really true,” Chen said.

Using a technique called X-ray crystallography, Chen and his team determined the various 3-D structures of large T as it interacts with the fuel molecule and changes shape in response. Putting these snapshots together, the team was able to visualize how the ring-shaped protein machine moves, separating and actively pumping DNA strands into its center.

The new report follows up on a key discovery the team made in 2003, when it became the first to describe the long-sought, static 3-D structure of large T, a task made difficult because of the protein’s size and complexity.

Chen’s recent work further elucidates one of the most critical moments in the life of a cell – the copying of its genetic material – that eventually leads to the division of a cell into two daughter cells.

This same moment also marks a focal point for cancer researchers intent on finding out how a healthy cell turns malignant.

In lab animals, the SV40 virus has long been known to cause cancers of the brain, bones, chest and lymphatic system. More recently, scientists have found DNA signatures of the SV40 virus in tumors from people with these same types of cancer.

While scientists continue to debate whether the virus caused the human cancers, the data are highly suggestive of a link, Chen said.

Although human exposure to SV40 is rare, many were accidentally exposed to the virus through contaminated polio vaccines administered in the 1960s in the U.S. Some suspect that in the former Soviet Union, contaminated vaccine was used as late as the 1980s.

The new finding provides valuable information for designing drugs that will block the infection of tumor viruses like SV40, as well as the related human papilloma virus, which causes cervical cancer, Chen said.

“The better we understand protein structure and function,” Chen said, “the better we can get at identifying anti-viral and anti-cancer drug targets.” said Chen, who has been busy setting up a new X-ray crystallography facility at the college.

What’s more, large T antigen’s similarities to proteins that initiate DNA copying in human cells have made it a powerful model for molecular biologists.

Chen’s new description of how large T works as a molecular machine – its parts “move in unison, like a jellyfish moves in the water” – has already altered expectations about how its human counterparts may work.

“Once you have the structure of a protein, if you really know how the parts come together and how they move,” Chen said, “you can find out a lot about what the protein does and how it does it. It’s a very direct way to study function.”