Learnings from Protein Folding Projected onto Amyloid Misfolding

The 1990s saw a revolution in our understanding of the protein folding pathways of both disulfide-bond-containing proteins and purely conformational folders. High-resolution maps of the folding trajectories, made possible by innovative experimental design, revealed the presence of multiple intermediates, their formation and consumption, and the network of interactions between them that lead to the formation of the folded protein from its unfolded state. The same level of detail has heretofore remained elusive as far as the amyloid aggregation pathways of prion-like proteins are concerned. Nevertheless, a recent development that led to the resolution of intermediates in amyloidogenic trajectories, without resort to their separation, is likely to not only advance our basic understanding of the atomic- and molecular-level interactions guiding amyloid misfolding but also impact interventional efforts in their associated pathologies.