Prions are not rare, usually are not harmful and may even help organisms adapt, a new study in yeast suggests.
Prions are shape-shifting proteins that change function along with their shapes, and can convert other proteins of the same type to the new shape. Prions tend to clump together in tight groups known as amyloids. The most famous prion is PrP, a protein found in the brains of mammals that sometimes twists into an infectious form and causes mad cow disease in cattle, scrapie in sheep and Creutzfeldt-Jakob disease in people. Scientists are still trying to determine the function of the normal form of the protein.
Researchers at the Whitehead Institute for Biomedical Research in Cambridge, Mass., have discovered that prions may be more widespread than previously thought. Baker’s yeast was previously known to have six prion proteins. The team, led by Howard Hughes Medical Institute investigator Susan Lindquist, reports in the April 3 Cell that 19 additional baker’s yeast proteins contain prion-forming domains — a structure within the protein that allows it to change shape and spread the altered form to other proteins. The researchers fully characterized one of the proteins, Mot3p, and found that it meets the criteria for a prion, bringing the number of confirmed prions in the yeast to seven.
“It was suspected by yeast prion researchers that prion formation is a widespread phenomenon, at least in yeast,” says Yury Chernoff, a biologist at the Georgia Institute of Technology in Atlanta and editor in chief of the journal Prion.
But other researchers thought prions were probably rare. The new study
“makes a huge step forward by experimentally confirming that there is a large number of domains exhibiting prion properties,” Chernoff says.
Only two prions are known to exist in organisms other than baker’s yeast, says Randal Halfmann, a coauthor of the new study. At the amino acid level, those two prions have little resemblance to known yeast prions.
But several of the known yeast prions have some common features, such as high concentrations of the amino acids asparagine and glutamine in the prion-forming region. Halfmann and Simon Alberti, also of the Whitehead Institute, trained a computer program to recognize protein regions that resemble those of four known yeast prions.
Computer searches of the yeast genome revealed that about 200 proteins contain regions similar to prion-forming domains. To narrow their search for new prions, Alberti and Halfmann tested 100 of the prion candidates for the ability to clump inside the yeast and form stable aggregates in the test tube.
All of the candidates aggregated in the yeast and all did so under certain conditions in the test tube, Alberti says, but most probably aren’t prions. The team did find that 19 of the strongest aggregators likely are new prions.
One of the strongest candidates, Mot3p, passed more biochemical and biological tests and can be declared a prion, the researchers say. Mot3p’s normal function is to regulate activity of many yeast genes, including some involved in building the yeast’s cell wall. In the altered form, Mot3p loses that ability to turn off production of certain cell wall components. Cells that carry that form build cell walls that would help them withstand certain environmental conditions that yeast with normal cell walls couldn’t tolerate.
“In the context of yeast, these proteins are not pathogenic but can be advantageous under certain conditions,” says Sina Ghaemmaghami, a biochemist at the Institute for Neurodegenerative Diseases at the University of California, San Francisco. Other prions may also exist in mammals, he predicts.
“It’s certainly plausible, and I’d say it’s even likely.”
Prions may help baker’s yeast “hedge their bets” on what conditions they may encounter in the future. The yeast don’t have to alter their genes if they can switch key proteins to conformations that offer survival advantages.
The researchers limited their search to proteins with domains similar to already known yeast prions, but other criteria might identify many other prions.
“It is logical to suggest that there are even more prions around,” Chernoff says. “And it is hard to believe that only yeast are so special. Indeed, protein-based inheritance of phenotypic traits can no longer be ignored.”