One of the unexplained questions facing prion researchers is how a single prion can apparently assume different conformations — with each conformation having different disease or phenotypic properties. Previous structural studies of prions had not yielded a clear understanding of the basis of strains because the prion protein is large and complex. Due to the size and complexity of prions, studies utilizing x-ray crystallography, a technique commonly used to determine the structure of proteins and other molecules, have been limited to short peptide fragments of the prion protein.

“There have been a number of fairly low-resolution pictures of prions that more or less proved that these different strains were in different conformations; but they really hadn’t established the nature of the different conformations,” Weissman said. “It was really a big black box. We basically didn’t have the conformation of any single prion, let alone the two prion protein strains in two different conformations.”
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““In our minds, our findings brought to a certain level of closure the understanding of the structural differences underlying strains,” said Weissman. “Now we understand the structural differences. We also have an idea how those differences lead to the differences in physical properties, and, in turn, how these differences in the physical properties lead to the phenotypic differences. We are starting to go all the way from the structural understanding of the different strains up to in vivo understanding of why they cause different behaviors inside the cell.”

Weissman noted that the findings offer a broader lesson to researchers studying prions and other proteins whose misfolding can cause disease. “Certainly, a bottom line from this study is that the rules of protein folding and the rules of protein misfolding are fundamentally different,” he said. “In many ways, we have to relearn basic principles of how proteins misfold. We have to forget many of the rules we learned from textbooks about protein folding because they are not necessarily applicable.”