Disaggregating chaperones: an unfolding story.

Détails

ID Serval
serval:BIB_02549A19D67F
Type
Article: article d'un périodique ou d'un magazine.
Sous-type
Synthèse (review): revue aussi complète que possible des connaissances sur un sujet, rédigée à partir de l'analyse exhaustive des travaux publiés.
Collection
Publications
Titre
Disaggregating chaperones: an unfolding story.
Périodique
Current Protein and Peptide Science
Auteur(s)
Sharma S.K., Christen P., Goloubinoff P.
ISSN
1875-5550[electronic], 1389-2037[linking]
Statut éditorial
Publié
Date de publication
2009
Peer-reviewed
Oui
Volume
10
Numéro
5
Pages
432-446
Langue
anglais
Résumé
Stress, molecular crowding and mutations may jeopardize the native folding of proteins. Misfolded and aggregated proteins not only loose their biological activity, but may also disturb protein homeostasis, damage membranes and induce apoptosis. Here, we review the role of molecular chaperones as a network of cellular defenses against the formation of cytotoxic protein aggregates. Chaperones favour the native folding of proteins either as "holdases", sequestering hydrophobic regions in misfolding polypeptides, and/or as "unfoldases", forcibly unfolding and disentangling misfolded polypeptides from aggregates. Whereas in bacteria, plants and fungi Hsp70/40 acts in concert with the Hsp100 (ClpB) unfoldase, Hsp70/40 is the only known chaperone in the cytoplasm of mammalian cells that can forcibly unfold and neutralize cytotoxic protein conformers. Owing to its particular spatial configuration, the bulky 70 kDa Hsp70 molecule, when distally bound through a very tight molecular clamp onto a 50-fold smaller hydrophobic peptide loop extruding from an aggregate, can locally exert on the misfolded segment an unfolding force of entropic origin, thus destroying the misfolded structures that stabilize aggregates. ADP/ATP exchange triggers Hsp70 dissociation from the ensuing enlarged unfolded peptide loop, which is then allowed to spontaneously refold into a closer-to-native conformation devoid of affinity for the chaperone. Driven by ATP, the cooperative action of Hsp70 and its co-chaperone Hsp40 may thus gradually convert toxic misfolded protein substrates with high affinity for the chaperone, into non-toxic, natively refolded, low-affinity products. Stress- and mutation-induced protein damages in the cell, causing degenerative diseases and aging, may thus be effectively counteracted by a powerful network of molecular chaperones and of chaperone-related proteases.
Mots-clé
Adenosine Diphosphate/chemistry, Adenosine Triphosphate/chemistry, Animals, Biochemistry/methods, Chaperonin 60/chemistry, Escherichia coli/metabolism, HSP70 Heat-Shock Proteins/chemistry, Humans, Models, Biological, Molecular Chaperones/chemistry, Mutation, Protein Denaturation, Protein Folding
Pubmed
Web of science
Création de la notice
23/11/2009 14:23
Dernière modification de la notice
20/08/2019 13:24
Données d'usage