RESUMO
In the densely populated intracellular milieu, polypeptides are at constant risk of nonspecific interactions and aggregation, posing a threat to essential cellular functions. Cells rely on a network of protein folding factors to deal with this challenge. The Hsp60 family of molecular chaperones, which depend on ATP for function, stands out in the proteostasis network by a characteristic structure comprising two multimeric rings arranged back to back. This review provides an updated overview of GroEL, the bacterial Hsp60, and its GroES (Hsp10) cofactor. Specifically, we highlight recent breakthroughs in understanding the intricate folding mechanisms of the GroEL-GroES nanomachine and explore the newly discovered interaction between GroEL and the chaperedoxin CnoX. Despite considerable research on the GroEL-GroES system, numerous questions remain to be explored.
Assuntos
Chaperonina 10 , Chaperonina 60 , Dobramento de Proteína , Chaperonina 60/metabolismo , Chaperonina 60/química , Chaperonina 60/genética , Chaperonina 10/metabolismo , Chaperonina 10/química , Ligação Proteica , Bactérias/metabolismo , Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genéticaRESUMO
Hsp60 chaperonins and their Hsp10 cofactors assist protein folding in all living cells, constituting the paradigmatic example of molecular chaperones. Despite extensive investigations of their structure and mechanism, crucial questions regarding how these chaperonins promote folding remain unsolved. Here, we report that the bacterial Hsp60 chaperonin GroEL forms a stable, functionally relevant complex with the chaperedoxin CnoX, a protein combining a chaperone and a redox function. Binding of GroES (Hsp10 cofactor) to GroEL induces CnoX release. Cryoelectron microscopy provided crucial structural information on the GroEL-CnoX complex, showing that CnoX binds GroEL outside the substrate-binding site via a highly conserved C-terminal α-helix. Furthermore, we identified complexes in which CnoX, bound to GroEL, forms mixed disulfides with GroEL substrates, indicating that CnoX likely functions as a redox quality-control plugin for GroEL. Proteins sharing structural features with CnoX exist in eukaryotes, suggesting that Hsp60 molecular plugins have been conserved through evolution.
Assuntos
Chaperonas Moleculares , Dobramento de Proteína , Microscopia Crioeletrônica , Chaperonas Moleculares/metabolismo , Oxirredução , Chaperoninas/química , Chaperoninas/metabolismo , Chaperonina 60/química , Chaperonina 10/metabolismoRESUMO
How proteins fold and are protected from stress-induced aggregation is a long-standing mystery and a crucial question in biology. Here, we present the current knowledge on the chaperedoxin CnoX, a novel type of protein folding factor that combines holdase chaperone activity with a redox protective function. Focusing on Escherichia coli CnoX, we explain the essential role played by this protein under HOCl (bleach) stress, discussing how it protects its substrates from both aggregation and irreversible oxidation, which could otherwise interfere with refolding. Finally, we highlight the unique ability of CnoX, apparently conserved during evolution, to cooperate with the GroEL/ES folding machinery.