Chaperonin-mediated folding by GroEL-GroES. (a) Space-filling model of an asymmetric GroEL/GroES chaperonin complex showing GroES bound as a dome-shaped molecule to the upper GroEL ring with the lower GroEL ring open. The cavity of the lower ring displays a hydrophobic surface (yellow) that can accept non-native polypeptides exposing hydrophobic surface, while the cavity of the upper GroES-bound ring has displaced the hydrophobic surfaces away from the cavity, substituting them with hydrophilic surface (blue) that may serve to favor folding of the encapsulated polypeptide within this cavity. (b) Rigid body movements, associated with GroES binding to a GroEL ring, entail the elevation and twisting of the GroES-bound GroEL apical domains. This conformational change removes the hydrophobic surface from the cavity and replaces it with hydrophilic surface. Reproduced with permission from Nature (38). (c) Action of ATP binding and hydrolysis to advance the chaperonin cycle. ATP (designated as T; ADP as D) binds with positive cooperativity within one GroEL ring, but with negative cooperativity between rings, so that ATP effectively occupies only one ring at a time. This establishes the asymmetry of the system, which is reinforced by the nucleotide requirement for GroES binding. Non-native polypeptide binds to the open ring of an asymmetric complex (first panel), and GroES binding to the same ring forms a folding-active complex and triggers polypeptide folding (second panel). The lifetime of this complex is determined by ATP hydrolysis in the GroES-bound ring, which weakens the interaction between GroES and GroEL (third panel). Binding of ATP and polypeptide to the opposite ring (fourth panel) then discharges GroES and the polypeptide, either in the native state (N) or one committed to it (I_c) or in a still non-native state (I_uc) that can rebind to GroEL and try again to refold (fifth panel). Binding to an open GroEL ring may be associated with an unfolding action. Note that the rings oscillate back and forth as polypeptide-accepting and then folding-active, a function of the asymmetric binding of ATP/GroES. cis, binding of GroES and polypeptide to the same GroEL ring. Reproduced with permission from Current Opinion in Structural Biology (37).