Protein folding in the cell: competing models of chaperonin function.

The long-standing view that polypeptide chains newly synthesized inside cells fold spontaneously to their functional conformations in an energy-independent fashion derives from the observation that many pure denatured proteins will refold spontaneously in vitro when the denaturant is removed. This view is being challenged by the alternative proposal that in vivo many chains need to be helped to fold correctly by preexisting proteins acting as molecular chaperones, some of which hydrolyse ATP. The need for molecular chaperones arises because of the high concentrations of transiently interacting protein surfaces inside cells permit the formation of incorrect nonfunctional structures. The best-studied family of molecular chaperones are called the chaperonins, the archetypal examples being the GroEL and GroES proteins of Escherichia coli. The chaperonins increase the yield of correctly refolded polypeptide chains, both by decreasing their propensity to aggregate with one another and by allowing polypeptides kinetically trapped in incorrect conformations to make fresh attempts to refold into the functional conformations. The mechanisms by which the chaperonins achieve these remarkable results are currently under debate. This review surveys competing models for chaperonin action, and emphasizes the importance when evaluating these models of considering the intracellular environment in which the chaperonins have evolved to function.