Chaperonins as protein-folding machines

The Escherichia coli chaperone GroEL epitomizes the group of chaperone proteins termed as chaperonins. The wealth of structural and functional information available for GroEL, and its accessory protein, the co-chaperonin GroES, has been of much value in deciphering the role of chaperonins in facilitating the folding of substrate proteins in the cell. The chaperonin machinery has a complex architecture which can undergo dramatic structural rearrangements upon interaction with GroES and nucleotides. Although the reaction cycle of GroEL binding with ATP/ADP as well as GroES is understood in some detail, the kinetic and structural details of the effect of the reaction cycle on the refolding polypeptide are only beginning to be understood. This review discusses the mechanism by which the GroEL/ES/ATP cycle can effect the correct folding of an unfolded substrate, or can even rescue some misfolded or kinetically trapped intermediates. The classical definition of chaperonin action is prevention of intermolecular aggregation, by binding partially-folded molecules, and allowing folding to take place in a ‘cage of infinite dilution’. More recent studies have, however, indicated that the chaperonin machinery plays a more active role in facilitating the folding reaction, by altering the energy landscape available to the substrate polypeptide for folding. New data has been analysed, and discussed not only in terms of how they have improved our understanding of chaperonin function, but also in terms of the important new issues that have been raised.