BYU experts unravel 'G proteins'

BYU researchers have unraveled the mystery of certain proteins involved in everything from heart rate to brain function and cancer growth.

The scientists discovered the mechanism for the assembly of G proteins, which are involved in cell signaling and are essential for responses to hormones, neurotrasmitters and more, said lead investigator Barry Willardson, associate professor of biochemistry at Brigham Young University. The findings are published today in the Journal of the European Molecular Biology Organization.

G proteins are a complex of three different subunits — alpha, beta and gamma. Beta and gamma "fold" together to activate enzymes and ion channels in the cells. The BYU research explains how those two subunits associate.

The G protein-coupled receptors on the surface of cells are the biggest class of receptors in the human genome, Willardson said. About half of all pharmaceuticals are targeted to these receptors. People who take beta blockers for heart disease, Prozac for depression, Claritin for allergies, Tagamet for indigestion, for example — the list is long — have all experienced the importance of G protein signaling in cell processing.

"If we know how G protein signaling works in cells, it gives you all that many more options to address these diseases," Willardson said.

The team's discovery answers a major biomedical question: How did the beta and gamma subunits fold together from their separate components?

The key is the role the protein called phosducin-like protein (PhLP, pronounced "flip") plays to help body cells regulate themselves when they are externally stimulated, Willardson said. For 12 years, researchers have known that PhLP is involved in G proteins signaling, but not how. Until now.

"There were not many hints, so this made a splash," said Willardson. "Eventually, this kind of research leads to treatments."

For a decade, scientists have tried to figure out what PhLP did. They knew it bound to the gamma and beta subunits but first thought it inhibited signaling, Willardson said. Groups working with single-cell organisms found that, when they knocked out the gene for PhLP, the opposite of what was expected happened.

Willardson's team used a method called RNA interference to remove PhLP in mammalian cells. The result was no signaling, and no subunits of the G proteins being produced in the cell.

"We determined they were not coming together as a complex," he said.

They believe now that the PhLP stabilizes the beta in its fold (the subunits fold into complex shapes; beta, for instance, looks like "a propeller with seven blades," Willardson said) and that allows it to mesh in with gamma.