Partially native intermediates mediate misfolding of SOD1 in single-molecule folding trajectories

Supratik Sen Mojumdar, Zackary Scholl, Derek R. Dee, Logan Rouleau, Uttam Anand, Craig Garen and Michael T. Woodside ()
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Supratik Sen Mojumdar: University of Alberta
Zackary Scholl: University of Alberta
Derek R. Dee: University of Alberta
Logan Rouleau: University of Alberta
Uttam Anand: University of Alberta
Craig Garen: University of Alberta
Michael T. Woodside: University of Alberta

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Prion-like misfolding of superoxide dismutase 1 (SOD1) is associated with the disease ALS, but the mechanism of misfolding remains unclear, partly because misfolding is difficult to observe directly. Here we study the most misfolding-prone form of SOD1, reduced un-metallated monomers, using optical tweezers to measure unfolding and refolding of single molecules. We find that the folding is more complex than suspected, resolving numerous previously undetected intermediate states consistent with the formation of individual β-strands in the native structure. We identify a stable core of the protein that unfolds last and refolds first, and directly observe several distinct misfolded states that branch off from the native folding pathways at specific points after the formation of the stable core. Partially folded intermediates thus play a crucial role mediating between native and non-native folding. These results suggest an explanation for SOD1’s propensity for prion-like misfolding and point to possible targets for therapeutic intervention.

Date: 2017
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DOI: 10.1038/s41467-017-01996-1

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