Development of free-energy-based models for chaperonin containing TCP-1 mediated folding of actin.
A free-energy-based approach is used to describe the mechanism through which chaperonin-containing TCP-1 (CCT) folds the filament-forming cytoskeletal protein actin, which is one of its primary substrates. The experimental observations on the actin folding and unfolding pathways are collated and then re-examined from this perspective, allowing us to determine the position of the CCT intervention on the actin free-energy folding landscape. The essential role for CCT in actin folding is to provide a free-energy contribution from its ATP cycle, which drives actin to fold from a stable, trapped intermediate I3, to a less stable but now productive folding intermediate I2. We develop two hypothetical mechanisms for actin folding founded upon concepts established for the bacterial type I chaperonin GroEL and extend them to the much more complex CCT system of eukaryotes. A new model is presented in which CCT facilitates free-energy transfer through direct coupling of the nucleotide hydrolysis cycle to the phases of actin substrate maturation.
Altschuler
Gabriel M
GM
Cancer Research UK Centre for Cell and Molecular Biology, Chester Beatty Laboratories, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
Willison
Keith R
KR
D000199:Actins / Q000378:metabolism*; D018834:Chaperonin 60 / Q000378:metabolism*; D056404:Chaperonin Containing TCP-1; D018833:Chaperonins / Q000378:metabolism*; D008956:Models, Chemical; D008958:Models, Molecular; D017510:Protein Folding
D000199:Actins; D018834:Chaperonin 60; D056404:Chaperonin Containing TCP-1; D018833:Chaperonins