Yeast proteins teach us about Alzheimer’s disease
Prions are infectious proteins formed when normal proteins misfold and start clumping together. In 1994, researchers discovered that prions can self-propagate in yeast and thus have properties of a gene. But what was the mechanism behind that protein self-propagation?
IRP researchers Rob Tycko, Ph.D., and Reed Wickner, M.D., showed that the infectious amyloid of the prion domains of several yeast prions (Sup35p, Ure2p and Rnq1p) have a parallel flat sheet architecture. In this case, and contrary to the long-standing tenet that amino acid sequence determines protein folding, the overall amino acid composition of a polypeptide (and not the sequence itself) seems to determine the protein’s ability to become a prion.
Not only does this research help explain the mechanism behind prion self-propagation, but it has broad significance in understanding several common human diseases that feature amyloids, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and type 2 diabetes.
Shewmaker, F., Ross, E.D., Tycko, R., and Wickner, R. B. (2008). Amyloids of shuffled prion domains that form prions have a parallel in-register beta-sheet structure. Biochemistry 47(13), 4000-4007.
Kryndushkin, D. S., Wickner, R. B. and Tycko, R. (2011). The core of Ure2p prion fibrils is formed by the N-terminal segment in a parallel cross-beta structure: evidence from solid-state NMR. J. Mol. Biol. 409(2), 263 – 277.
Lu, J.Z., Qiang, W., Yau, W.M., Schwieters, C.D., Meredith, S.C., and Tycko, R. (2013). Molecular structure of beta-amyloid fibrils in Alzheimer’s disease brain tissue. Cell 154(6), 1257-68.
This page was last updated on Friday, January 14, 2022