How chaperones fold proteins

Chaperones are a functionally related group of proteins assisting protein folding in the cell under physiological and stress conditions. They share the ability to recognize and bind nonnative proteins thus preventing unspecific aggregation. The underlying functional principles of the different chaperone classes are beginning to be understood. A landmark feature of molecular chaperones is the involvement of energy-dependent reactions in the folding process. Nucleotide binding to ATP-dependent chaperones (e.g. GroEL, Hsp70, Hsp90) leads to sometimes large conformational changes in the chaperone which allow to shift between high- and low-affinity states for substrate proteins. Interestingly, the ATPase activity which is the key determinant for functional cycles is tightly regulated by a set of co-chaperones. While for ATP-dependent chaperones binding sites for nucleotide and protein are found in one protein, in the case of ATP-independent chaperones (e. g. sHsps, SecB) the energy-dependent step is performed by another chaperone (Hsp70, SecA). Therefore, the ATP-independent chaperones can be regarded as efficient 'holding' components. Cooperation of different chaperone machineries creates a synergistic network of folding helpers in the cell, which allows to maintain protein homeostasis under conditions nonpermissive for spontaneous folding.