Chaperonin-mediated protein folding

Molecular chaperones are required to assist folding of a subset of proteins in Escherichia coil. We describe a conceptual framework for understanding how the GroEL-GroES system assists misfolded proteins to reach their native states. The architecture of GroEL consists of double toroids stacked back- to-back. However, most of the fundamentals of the GroEL action can be descr ibed in terms of the single ring. A key idea in our framework is that, with coordinated ATP hydrolysis and GroES binding, GroEL participates actively by repeatedly unfolding the substrate protein (SP), provided that it is tra pped in one of the misfolded states. We conjecture that the unfolding of SP becomes possible because a stretching force is transmitted to the SP when the GroEL particle undergoes allosteric transitions. Force-induced unfoldin g of the SP puts it on a higher free-energy point in the multidimensional e nergy landscape from which the SP can either reach the native conformation with some probability or be trapped in one of the competing basins of attra ction (i.e., the SP undergoes kinetic partitioning). The model shows, in a natural way, that the time scales in the dynamics of the allosteric transit ions are intimately coupled to folding rates of the SP. Several scenarios f or chaperonin-assisted folding emerge depending on the interplay of the tim e scales governing the cycle. Further refinement of this framework may be n ecessary because single molecule experiments indicate that there is a great dispersion in the time scales governing the dynamics of the chaperonin cyc le.