Forces Driving Chaperone Action

It is still unclear what molecular forces drive chaperone-mediated protein folding. Here, we obtain a detailed mechanistic understanding of the forces that dictate the four key steps of chaperone-client interaction: initial binding, complex stabilization, folding, and release. Contrary to the common belief that chaperones recognize unfolding intermediates by their hydrophobic nature, we discover that the model chaperone Spy uses long-range electrostatic interactions to rapidly bind to its unfolded client protein Im7. Short-range hydrophobic interactions follow, which serve to stabilize the complex. Hydrophobic collapse of the client protein then drives its folding. By burying hydrophobic residues in its core, the client’s affinity to Spy decreases, which causes client release. By allowing the client to fold itself, Spy circumvents the need for client-specific folding instructions. This mechanism might help explain how chaperones can facilitate the folding of various unrelated proteins. [Display omitted] •Chaperone Spy is lured to client protein by electrostatic, not hydrophobic forces•Client folding triggers its own release, making the chaperone self-regulating•Client self-folding eliminates the need for client specific folding instructions•This explains how chaperones can facilitate the folding of unrelated proteins A chaperone is lured to its unfolded client by electrostatic rather than hydrophobic interactions, and a sequential transition between these two forces promotes folding and release, all without ATP.