CHAPERONIN-FACILITATED PROTEIN-FOLDING - OPTIMIZATION OF RATE AND YIELD BY AN ITERATIVE ANNEALING MECHANISM

We develop a heuristic model for chaperonin-facilitated protein foldin g, the iterative annealing mechanism, based on theoretical description s of ''rugged'' conformational free energy landscapes for protein fold ing, and on experimental evidence that (i) folding proceeds by a nucle ation mechanism whereby correct and incorrect nucleation lead to fast and slow folding kinetics, respectively, and (ii) chaperonins optimize the rate acid yield of protein folding by an active ATP-dependent pro cess. The chaperonins GroEL and GroES catalyze the folding of ribulose bisphosphate carboxylase at a rate proportional to the GroEL concentr ation. Kinetically trapped folding-incompetent conformers of ribulose bisphosphate carboxylase are converted to the native state in a reacti on involving multiple rounds of quantized ATP hydrolysis by GroEL. We propose that chaperonins optimize protein folding by an iterative anne aling mechanism; they repeatedly bind kinetically trapped conformers, randomly disrupt their structure, and release them in less folded stat es, allowing substrate proteins multiple opportunities to find pathway s leading to the most thermodynamically stable state. By this mechanis m, chaperonins greatly expand the range of environmental conditions in which folding to the native state is possible. We suggest that the de velopment of this device for optimizing protein folding was an early a nd significant evolutionary event.