Mad cows and crazy proteins: understanding how the prion protein folds and misfolds at the single-molecule level

Seminar | May 8 | 12-1 p.m. | 177 Stanley Hall

 Michael T. Woodside, University of Alberta

 QB3 - California Institute for Quantitative Biosciences

Prion diseases like "mad cow" disease are caused by the protein PrP, which forms an incorrect structure that is both toxic to neurons and infectious, in the sense that it can propagate the misfolding. The mechanisms by which misfolded PrP forms and spreads remain poorly understood. I will discuss our studies of PrP misfolding in the single-molecule regime, using high-resolution optical tweezers to observe the structural dynamics of individual PrP molecules as they either fold natively or misfold and aggregate into larger structures. Studying isolated hamster PrP molecules, we found that they could form several types of misfolded structures, but the misfolding was short-lived and unstable compared to the native state. When two PrP molecules were held together to form a dimer, however, a stable misfolded state was formed instead of the native structure, driven by the formation of a key non-native intermediate. From reconstructing the energy landscape for the misfolding, we also found that the microscopic dynamics during misfolding were 1000-fold slower than native folding, reflecting a much rougher energy landscape. Turning to the effects of a drug with known anti-prion activity, we found that not only does it stabilize the native structure, altering the energy landscape for unfolding, but it also mimics the action of natural chaperones in the cell that reduce misfolding by preferentially preventing the formation of stable misfolded structures. Finally, we investigated the differences in the folding of PrP from species with different disease susceptibility, to determine what features of the folding may be linked with susceptibility to disease.