Viral proteins lie down on the job.

Flaviviruses, responsible for diseases such as dengue, yellow fever, Japanese encephalitis, and tick-borne encephalitis, are deadlier--but less menacing to look at--than their influenza- causing cousins. Flu viruses bristle with spiky surface proteins that they use to insinuate themselves into the cells they infect. Flaviviruses' surface proteins, in contrast, appear to conform to the pathogen's spherical shape, judging from the first three- dimensional pictures of these structures.

This stark difference suggests that viruses have evolved many ways to infiltrate their hosts. "I think this is really exciting. We know so very little about how viruses infect cells," says Peter S. Kim of the Whitehead Institute for Biomedical Research in Cambridge, Mass.

Researchers at Harvard University and the University of Vienna in Austria obtained the new images by first crystallizing the main surface protein of the tick-borne encephalitis (TBE) virus. They then shone intense X rays through this crystal and deduced the protein's structure from the pattern of light produced by the X rays deflecting off atoms.

The resulting viral protein snapshot, described in the May 25 Nature, surprised everyone. It looked nothing like hemagglutinin, the influenza surface protein whose structure had been revealed in 1981.

"Everyone thought it would be spikes. [Hemagglutinin] has been the model for 14 years," says Harvard's Felix A. Rey, a coauthor of the report.

On the flu virus, three hemagglutinin molecules combine to produce the characteristic spikes. A flavivirus surface protein normally pairs with only one other to form a molecule known as a dimer. The X-ray data show the dimer to be rod-shaped and slightly bent in the middle where the two proteins join, the researchers say.

The dimer's curvature matches that of the virus itself, leading Rey and his colleagues to theorize that rather than jutting upward, dimers cover the virus horizontally. "The biggest surprise is that it's lying down flat. That's very unusual," says Michael G. Rossman of Purdue University in West Lafayette, Indiana, coauthor of an accompanying commentary in Nature.

In 1993, Kim and Chavela M. Carr proposed a mechanism, based on the 1981 picture of hemagglutinin, by which the flu virus penetrates cells. They argued that deep within each hemagglutinin molecule is a small protein fragment called a fusion peptide. When a virus encounters a cell membrane, a springlike device launches this fusion peptide into the membrane, like a speargun lancing a whale (SN: 5/29/93, p.340).

This theory was confirmed in 1994, but the structure of the flavivirus surface protein reveals that the method of attacking cells used by the influenza virus "is not the only way nature has solved the problem," says Kim.

Rey and his colleagues think that when the TBE virus meets a cell, the protein dimers on the virus' surface break apart and link up in threes to form trimers. As this happens, they say, each individual protein dramatically rearranges its shape, uncovering its own fusion peptide.

"This fusion peptide sits [inside the protein] snugly. When the dimer disassociates, the peptide then becomes accessible," says Rey. Researchers hope to confirm this theory by snapping an image of the TBE viral protein in its trimer form.

The newly revealed dimer structure also indicates which parts of the viral protein the immune system and other cells in the body see--knowledge that may help scientists trying to develop vaccines for flaviviral diseases.