Recent and future grand challenges in protein folding, misfolding, and degradation
Abstract
Our general aim is to better understand the biophysical and biochemical principles that govern nascent or stress-destabilized proteins to unfold and re/fold to their native state or, alternatively, choose to misfold and aggregate into cytotoxic species, which in animals can cause degenerative diseases.
When a protein is first artificially unfolded by a chaotropic agent, it may thereafter spontaneously refold into its three dimensional native state without necessitating additional steric information from other macromolecules in the solution. Anfinsen (1973), thus masterfully demonstrated that the primary sequence of the amino acids contains sufficient information for polypeptides to reach their native functional three-dimensional structure. Yet, the yields of such in vitro protein refolding assays are typically low and a large fraction of the polypeptide precipitates into insoluble aggregates.
Living cells cannot accumulate high concentrations of chaotropic agents to specifically unfold potentially toxic aggregates, while leaving intact the surrounding native proteins. Instead they express molecular chaperones that can specifically recognize and bind with high-affinity to the misfolded polypeptides, which are to be unfolded into intermediates that can, thereafter, spontaneously refold into low-affinity native products (Hinault et al., 2006; Priya et al., 2013). In the cell, heat-stress can cause the partial transient opening of native proteins, typically at hinges between…
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