Protein chaperones and the protein unfolding problem

After or during translation, most proteins must fold into well determined three-dimensional structures to be functional. This process, though, can be perturbed leading to errors in the form of misfolded proteins. Protein misfolding can also take place when natively folded proteins are exposed to different kind of stresses. Molecular chaperones are Nature’s solution to this problem, being able to rescue conformationally damaged polypeptides, bringing them back to the productive folding pathway by unfolding misfolded conformations. While protein folding, the process allowing proteins to reach their native functional state, is for the most part autonomous, its counterpart, protein unfolding, takes place against an energy gradient, and must thus use the energy obtained from ATP hydrolysis. Some molecular chaperones are thus active unfoldases. In this chapter, I am going to review our current understanding of the main unfolding chaperones and briefly discussing the potential role of non-unfolding chaperones. The parallel with RNA chaperones shows that macromolecular unfolding is a widespread strategy in the cell.