CURRENT

Protein Portrait

For years scientists have struggled to get a look at the structure of the capsid protein that serves as the building block of an inner shell of the human immunodeficiency virus. It’s important work, since picturing the otherwise invisible capsid could help scientists discern its vital role in the virus’ life cycle. That knowledge, in turn, would likely lead to new and more effective ways of combatting HIV/AIDS.

“The capsid shell acts as an ‘invisibility cloak’ that hides the virus’ genetic information, the genome, while it is being copied in a hostile environment for the virus,” says Stefan Sarafianos, a professor of molecular microbiology and immunology and biochemistry and Chancellor’s Chair of Excellence in molecular virology.

“Fine-tuned capsid stability is critical for successful infection: too stable a capsid shell and the cargo is never delivered properly; not stable enough and the contents are detected by our immune defenses, triggering an antiviral response. Capsid stability is a key to the puzzle, and you have to understand its structure to solve it.”

Until recently, the clearest image of that structure had been that of a mutated protein. But now Sarafianos, MU graduate student Anna Gres and their laboratory team have for the first time captured images of the capsid protein in its natural state, creating the most complete model yet of an HIV capsid protein. The breakthrough was possible thanks to a sophisticated deployment of X-ray crystallography, a technology that takes advantage of the fact that X-rays are diffracted by molecules’ atomic-level crystalline structure.

By interpreting how the X-rays scattered when they ricocheted off the proteins, the researchers were able to develop a 3-D map.

“But the 3-D map doesn’t make sense until we make an atomic model of the protein to fit in that map,” says Karen Kirby, a study co-author and research scientist at the Bond Life Sciences Center. “The map is just a grid that you can’t really interpret unless you put a model into it to see ‘Ok, it looks like this part is here, and that part is there, and this is how the protein is put together.’”

Gres constructed the model, which revealed “ordered” water molecules at areas between the viral proteins.

“We thought, ‘How could some simple water molecules really be of consequence?’” Sarafianos says. “But when we looked carefully, we realized there are thousands of waters that help stabilize the complex capsid scaffold. We hypothesized that this is an essential part of the stability of the whole capsid assembly.”

To test that hypothesis, they dehydrated the crystals using chemicals. This caused the proteins to change shape, suggesting that water molecules help the capsid shell to remain flexible and assume different forms, Sarafianos says. Such elasticity may be critical for the life cycle of the virus.

Further investigations, he adds, funded in part with support from a recent five-year, $2.28 million grant from the National Institutes of Health, will clarify this and other questions.

The current study was published in the July 3 issue of the journal Science.

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