Friends in need: How chaperonins recognize and remodel proteins that require folding assistance

Abstract

Chaperonins are biological nanomachines that help newly translated proteins to fold by rescuing them from kinetically trapped misfolded states. Protein folding assistance by the chaperonin machinery is obligatory in vivo for a subset of proteins in the bacterial proteome. Chaperonins are large oligomeric complexes, with unusual seven fold symmetry (group I) or eight/nine fold symmetry (group II), that form double-ring constructs, enclosing a central cavity that serves as the folding chamber. Dramatic large-scale conformational changes, that take place during ATP-driven cycles, allow chaperonins to bind misfolded proteins, encapsulate them into the expanded cavity and release them back into the cellular environment, regardless of whether they are folded or not. The theory associated with the iterative annealing mechanism, which incorporated the conformational free energy landscape description of protein folding, quantitatively explains most, if not all, the available data. Misfolded conformations are associated with low energy minima in a rugged energy landscape. Random disruptions of these low energy conformations result in higher free energy, less folded, conformations that can stochastically partition into the native state. Two distinct mechanisms of annealing action have been described. Group I chaperonins (GroEL homologues in eubacteria and endosymbiotic organelles), recognize a large number of misfolded proteins non-specifically and operate through highly coordinated cooperative motions. By contrast, the less well understood group II chaperonins (CCT in Eukarya and thermosome/TF55 in Archaea), assist a selected set of substrate proteins. Sequential conformational changes within a CCT ring are observed, perhaps promoting domain-by-domain substrate folding. Chaperonins are implicated in bacterial infection, autoimmune disease, as well as protein aggregation and degradation diseases. Understanding the chaperonin mechanism and the specific proteins they rescue during the cell cycle is important not only for the fundamental aspect of protein folding in the cellular environment, but also for effective therapeutic strategies.

Keywords: GroEL; GroES; aggregation; chaperonins; folding assistance; misfolding; substrate recognition.

FIGURE 1

Prototypes of chaperonin classes. (A) Group I chaperonin GroEL and its co-chaperonin GroES (purple) (B) Group II chaperonin thermosome. Three domains, equatorial (red), intermediate (green), and apical (yellow), are distinguished within each subunit. The domains belonging to one subunit of each chaperonin are higlighted. Adapted from (Ditzel et al., 1998).

FIGURE 2

Reaction hemicycle of GroEL illustrating the substrate protein (SP) folding assistance. EL and ES stand for GroEL and GroES respectively. The GroEL T state has a high affinity for SP binding. Upon ATP and GroES binding, the SP is displaced into the expanded GroEL cavity, where productive folding can take place. Dissociation of the complex occurs upon the initiation of a folding reaction in the opposite GroEL ring. The structures of the T, R, and R″ states are known. Reproduced from (Stan et al., 2007) Ⓒ(2007) National Academy of Sciences.

FIGURE 3

Energy landscape perspective of the chaperonin annealing action.

FIGURE 4

(A) Contacts between GroEL helices H and I (cyan) and the GroES mobile loop (pink). Sidechains of the residues that form the closest contacts are shown in red (GroEL) and green (GroES). (B) Schematic representation of contacts between GroEL and GroES. Reproduced from Ref (Stan et al., 2005).