Protein homeostasis depends on the ability of molecular chaperones to assist
proteins with complex folding patterns to achieve their native state. An important
molecular chaperone found in the eukaryotic cytosol is the chaperonin containing
tailless complex polypeptide 1 (CCT, also called TRiC). CCT is composed of eight
homologous subunits, each with ATPase activity, that form a double ring complex with
protein folding cavities in the center of each ring. CCT folds primarily nascent
polypeptides that have yet to achieve their native state by binding the unfolded protein
in the folding cavity of the open, nucleotide-free conformation of CCT. Upon binding
and hydrolysis of ATP, CCT undergoes a conformational change that simultaneously
creates a lid over the folding cavity and releases the nascent protein into the cavity. The
protein is then allowed to fold in this confined space isolated from other proteins in the
cell. Dissociation of phosphate and ADP allows CCT to relax back into its open
conformation and release the protein if it has achieved its native conformation. Recent
studies suggest that CCT initially extends and unfolds at least some substrate proteins
by binding them at sites on opposite sides of the folding cavity. Interestingly, subunits
on one side of the CCT ring bind and hydrolyze ATP more effectively than subunits on
the other side, suggesting a sequential release mechanism first from one side and then
the other, effectively dictating the folding trajectory of the protein. The CCT folding
process is facilitated by co-chaperones that deliver substrates for folding, stabilize
folding intermediates or promote substrate release. In this manner, CCT and its cochaperones
accommodate the folding of many protein substrates with diverse folding
patterns.
Keywords: Protein folding, Molecular chaperone, Chaperonin, Substrate
recognition, Folding mechanism, Co-chaperone, Phosducin-like protein.
