Chaperonin-facilitated protein folding: optimization of rate and yield by an iterative annealing mechanism.
We develop a heuristic model for chaperonin-facilitated protein folding, the iterative annealing mechanism, based on theoretical descriptions of "rugged" conformational free energy landscapes for protein folding, and on experimental evidence that (i) folding proceeds by a nucleation mechanism whereby correct and incorrect nucleation lead to fast and slow folding kinetics, respectively, and (ii) chaperonins optimize the rate and yield of protein folding by an active ATP-dependent process. The chaperonins GroEL and GroES catalyze the folding of ribulose bisphosphate carboxylase at a rate proportional to the GroEL concentration. Kinetically trapped folding-incompetent conformers of ribulose bisphosphate carboxylase are converted to the native state in a reaction involving multiple rounds of quantized ATP hydrolysis by GroEL. We propose that chaperonins optimize protein folding by an iterative annealing mechanism; they repeatedly bind kinetically trapped conformers, randomly disrupt their structure, and release them in less folded states, allowing substrate proteins multiple opportunities to find pathways leading to the most thermodynamically stable state. By this mechanism, chaperonins greatly expand the range of environmental conditions in which folding to the native state is possible. We suggest that the development of this device for optimizing protein folding was an early and significant evolutionary event.
Todd
M J
MJ
Central Research and Development Department, DuPont Company Experimental Station, Wilmington, DE 19880-0402, USA.
Lorimer
G H
GH
Thirumalai
D
D
D000255:Adenosine Triphosphate / Q000378:metabolism; D018834:Chaperonin 60 / Q000378:metabolism*; D018833:Chaperonins / Q000502:physiology*; D007700:Kinetics; D008961:Models, Structural; D011487:Protein Conformation; D017510:Protein Folding; D012273:Ribulose-Bisphosphate Carboxylase / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
D018834:Chaperonin 60; D000255:Adenosine Triphosphate; D018833:Chaperonins; D012273:Ribulose-Bisphosphate Carboxylase