Caging helps proteins fold

Open Access
Publisher Website
Google Scholar
Abstract
How do proteins fold spontaneously? The quest to answer this question has led to significant developments on theoretical, experimental, and computational fronts in the last decade (1–7). A combination of approaches has provided a detailed understanding of the nature of pathways and the transition states that the polypeptide chain encounters as it traverses the rugged energy landscape. Even as our understanding of in vitro protein folding at infinite dilution has advanced, it has become urgent to address two additional issues of biological interest. (i) In vivo folding is not always a spontaneous event. A subset of proteins may require molecular chaperones. In an illuminating article in this issue of PNAS, Takagi et al. (8) provide a detailed study of five model proteins of varying native state architecture confined to cylindrical nanopores, which are meant to mimic the cavity of GroEL. Of all the molecular chaperones, the GroEL/GroES system from Escherichia coli, which assists folding of a fraction of cytosolic proteins, is the best understood. GroEL, a cylindrical barrel, consists of two heptameric rings stacked back-to-back giving rise to an unusual sevenfold symmetry about the axis of the cylinder (9). The annealing action of the chaperonin machinery (GroEL/GroES) is complex and involves large allosteric domain movements in GroEL in response to binding of the substrate protein (SP), ATP, and GroES (10, 11). The presence of a central cavity has led to the proposal that GroEL merely offers a protective environment in which SP folds as it would in infinite dilution. Indeed, for an undetermined duration out of the total of 10 sec of the chaperonin cycle, SP experiences confinement in the cylindrical cavity, whose maximum volume is ≈175,000 Å3. However, the annealing action of GroEL is due to the changes in the inner lining of the …