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The analysis required a special application of nuclear magnetic resonance spectroscopy, which enabled him to identify structural differences at the atomic level underlying these different phenotypes. The results, published in Nature in 2007, confirmed that the same protein can misfold into dramatically different prion conformations—which is why the phenotypes they produce can vary so significantly.
Some of the newest prion work takes a deeper look at multiple strains. The goal is to figure out how the amino acid sequence of a prion determines its configuration and how the resulting structures differ at the atomic level.
HHMI investigator David Eisenberg, a protein structure specialist at the University of California, Los Angeles, uses various types of x-ray crystallography techniques to study the structure of the amyloid proteins produced by prions.
In 2005, Eisenberg showed that when a protein converts to a prion, it polymerizes into an aggregate made up of tightly packed layers known as beta sheets (as opposed to the coiled alpha helices that dominate in the normal protein structure). The firmly bound beta sheets, held together by an interlocking of their side chains that Eisenberg has termed a “steric zipper,” give the prion its stable, tough properties. In fact, the sheets are so closely packed that they exclude water, making prions insoluble.
In a 2009 paper in Nature Structural & Molecular Biology, Eisenberg proposed an explanation of how a single protein gives rise to varying shapes of amyloids that specify different strains. Instead of DNA alterations, as in living organisms, prion strains are specified by structural changes that are sufficiently stable to perpetuate the strain identity in successive prions—and when they jump from cell to cell and animal to animal.
In one type of strain-determining mechanism, the same segment of a protein's amino acid sequence can specify different “packing” arrangements of the beta sheets. In an alternative mechanism, distinctive beta sheets are produced by different segments of the protein.
“Our hypothesis is that the differences in packing produce diverse amyloid fibrils, and these fibers cause different disease types,” says Eisenberg.
In fact, these variations that Eisenberg is finding at the most fundamental, atomic level may come full circle to explain the array of functions—some harmful, some helpful—found in prions ranging from yeast to humans.
Meanwhile, he and other scientists, including Si, Kandel, and Lindquist, are searching for evidence of the positive side of prions.
If that search is fruitful, Si has a radical proposal: “Prions have been so tightly linked to the diseases that if we find more of these positive functions, I think eventually we might have to come up with a new name for them.”