The Mechanism and Function of Group II Chaperonins

Abstract

Protein folding in the cell requires the assistance of enzymes collectively called chaperones. Among these, the chaperonins are 1 MDa ring-shaped oligomeric complexes that bind unfolded polypeptides and promote their folding within an isolated chamber in an ATP-dependent manner. Group II chaperonins, found in archaea and eukaryotes, contain a built-in lid that opens and closes over the central chamber. In eukaryotes, the chaperonin TRiC/CCT is hetero-oligomeric, consisting of two stacked rings of eight paralogous subunits each. TRiC facilitates folding of approximately 10% of the eukaryotic proteome, including many cytoskeletal components and cell cycle regulators. Folding of many cellular substrates of TRiC cannot be assisted by any other chaperone. A complete structural and mechanistic understanding of this highly conserved and essential chaperonin remains elusive. However, recent work is beginning to shed light on key aspects of chaperonin function, and how their unique properties underlie their contribution to maintaining cellular proteostasis.

Role of CCT chaperonin in the disassembly of mitotic checkpoint complexes

“…In their action in protein folding, chaperonins bind protein substrates in the absence of ATP, whereas their release is accompanied by the hydrolysis of ATP (17)(18)(19). We found that in this case, too, the dissociation of the chaperonin from mitotic checkpoint complexes requires ATP, as assayed by the release of CCT5 from immunoprecipitated complexes to supernatants (Fig.…”

“…A great body of previous work described actions of CCT/TRiC chaperonin in the folding of proteins to their native states (reviewed in refs. [17][18][19]. It is a complex composed of two rings of eight homologous subunits surrounding a central cavity, where folding is thought to take place.…”

“…It was also reported to be involved in the folding of physiologically important substrates such as the cell cycle regulators Cdc20 (24) and Plk1 (26), tumor suppressors p53 and VHL, and Gs subunits of signaling complexes (reviewed in ref. 19). CCT/TRiC chaperonins do not recognize specific amino acid sequence motifs in substrates, but appear to have a broad binding specificity to structures such as hydrophobic surfaces (27).…”

“…More minor proteins were identified as HSP70, tubulin and actin. Tubulin and actin are known to be associated with CCT/ TRiC for their folding (17)(18)(19). HSP70 is unlikely to be the disassembly factor because most of it eluted earlier than disassembly activity in ATP affinity chromatography ( Fig.…”

“…We find that Cdc20 is dissociated from BubR1 in MCC and in its subcomplexes by the action of chaperonin containing TCP1 or TCP1-Ring complex (CCT/TRiC), a complex previously known to have roles in protein folding (reviewed in refs. [17][18][19]. Along with the previously described pathways for MCC disassembly, the action of CCT/TRiC provides a mechanism for the complete dissociation of MCC into its free protein components and thus for the inactivation of the mitotic checkpoint.…”