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A promiscuous prion. S. cerevisiae (SC) and C. albicans (CA) prions won't mix (top), but both will coax a hybrid protein into prion fibers that remember the shape of the protein that seeded them (bottom).

Two-Faced Prions

Both "mad cow disease" and the sheep disease scrapie are caused by abnormally shaped proteins called prions, but only mad cow disease seems to have jumped into humans. Why? One idea is that some prions can assume more than one shape, which allows them to more easily invade a new host. Now research in yeast has backed up this theory.

Yeast cells contain prions which, although not infective, behave like mammalian prions. The hallmark behavior of both prion types is a promiscuous shape change: Once a normal prion protein adopts an abnormal shape, it will induce other proteins of the same type to do the same, causing them all to clump as insoluble aggregates. This isn't a haphazard process. Previous work showed that the Sup35 prion protein from the yeast species Saccharomyces cerevisiae cannot coax Sup35 from another yeast, Candida albicans, into a prion form, and vice versa. Scientists wondered what the structural basis for this species barrier was.

Curious, Jonathan Weissman and Peter Chien of the University of California, San Francisco, constructed a hybrid Sup35 protein that was part Saccharomyces and part Candida to see what would happen. After confirming that the hybrid protein acted like a prion when they substituted it for Sup35 in living Saccharomyces cells, Weissman and Chien took the hybrid protein to the test tube, where it still formed characteristic prion fibers. When they "seeded" the reaction with prion fibers, this sped up the aggregation. This worked with fibers made up of either the Saccharomyces protein or the Candida protein, suggesting that the hybrid was able to assume a shape that would match either kind.

Next, the researchers took these newly created fibers and added soluble prion protein to them from either Saccharomyces or Candida. The soluble Saccharomyces protein would join onto to the newly formed fibers--but only the ones that had been originally started by the aggregated Saccharomyces seeds, the duo reports in the 8 March issue of Nature. Likewise, the Candida protein hooked up only with fibers that had been seeded by Candida aggregates. Thus, the hybrid protein seemed to be able to remember either of two unique shapes.

If the mad cow prion, like the hybrid in the experiment, were able to adopt multiple shapes, that would make it more likely to infect other species, the authors speculate. But drawing conclusions about mammalian prions directly from the yeast work is difficult, because, as physical biochemist Peter Lansbury of Harvard Medical School in Boston points out, there are "huge differences" between the yeast and mammalian prions.

Related sites
J. S. Weissman lab home page
Susan Liebman's faculty page