Protein Folding, Misfolding, and Aggregation Observed Directly using Single-Molecule Force Spectroscopy
- Michael Woodside, University of Alberta, NINT/NRC
Thursday, February 21, 4:10 PM - Physics and Astronomy Colloquium
Biomedical & Physical Sciences Bldg., Rm. 1415
Most proteins reliably fold into specific "native" three-dimensional structures which are required to perform their function properly. When the folding process goes awry, however, non-native structures can result that lead to disease, with examples ranging from Alzheimer's to scurvy. My lab is studying the mechanisms driving such misfolding in two disease-related proteins, PrP (prion disease) and alpha-synuclein (Parkinson's). We use high-resolution optical tweezers to observe the conformational dynamics and structural properties of individual proteins as they either fold natively or misfold and aggregate. In the case of PrP, we have measured the conformational free-energy landscape for native folding of the protein, using it to determine the timescale for microscopic motion of the protein during the folding transition. We also found three distinct pathways leading to misfolding. In the case of alpha-synuclein, which is intrinsically disordered (in contrast to the well-defined structure of PrP), we observed transient structures formed by individual molecules. We have compared these to the structures formed by small oligomers of alpha-synuclein, finding that many different structures can form in the oligomers, the aggregation rate is size-dependent, and the aggregates grow in stability with size.