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

• DOI: 10.1038/s41467-017-01996-1
• Publication Date: 2017-11-27T10:19:38Z
• Authors: Supratik Sen Moju...; Zackary N. Scholl; Derek R. Dee; Logan Rouleau; Uttam Anand; Craig Garen; Michael T. Woodside
• Keywords: Folding (DSP implementation)

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