When a protein misfolds, the results can be disastrous. An incorrect change in the molecule’s shape can lead to diseases including Alzheimer’s and Huntington’s. But scientists have discovered that misfolded proteins can have a positive side in yeast, helping cells navigate the dicey current of natural selection by expressing a variety of hidden genetic traits.
What’s more, at the center of this process is a prion, a small protein found in the brain cell membrane. The distorted form of this protein is responsible for the mad cow disease and causes new Creutzfeld-Jakob disease in humans.
“This is the first time we’ve seen a prion affect a cell in a beneficial way that can determine the evolution of an organism,” says Heather True, lead author of the paper, which will appear August 15 in the online edition of the journal Nature.
Previously, True and Whitehead Institute Director Susan Lindquist reported that a particular yeast protein called Sup35 somehow altered the metabolic properties—or phenotype—of the cell when it “misfolded” into a prion state. Sup35 helps guide the process by which cells manufacture protein molecules. However, when Sup35 misfolds into its prion state, it forms amyloid fibers similar to those found in Alzheimer’s patients and causes the cell’s protein-producing machinery to go drastically awry.
More often than not, this is deleterious to the cell. In about 20% of the cases tested, however, the Whitehead team discovered that these new phenotypes afford the yeast cell a survival advantage.
“But we still didn’t know the molecular mechanisms behind this,” says True, a former postdoctoral researcher in the Lindquist lab, and now an assistant professor at Washington University, St. Louis. “How exactly did the prion change the appearance of the cell?”
The answer revealed a twist in the traditional understanding of how traits are inherited.
In order for Sup35 to ensure that the cell properly reads the protein recipes contained in genes, it focuses on what are called “stop codons”—sections of DNA that indicate exactly where in the gene a particular protein recipe ends. Sup35 ensures that the cell only translates material prior to these designated codons.
But when it misfolds into a prion conformation, Sup35 gets sloppy, and the cell reads beyond the stop codons, translating genetic information that previously had been dormant. As a result, the cell’s phenotype changes.