Disaggregating chaperones: an unfolding story.

Details

Serval ID
serval:BIB_02549A19D67F
Type
Article: article from journal or magazin.
Publication sub-type
Review (review): journal as complete as possible of one specific subject, written based on exhaustive analyses from published work.
Collection
Publications
Institution
Title
Disaggregating chaperones: an unfolding story.
Journal
Current Protein and Peptide Science
Author(s)
Sharma S.K., Christen P., Goloubinoff P.
ISSN
1875-5550[electronic], 1389-2037[linking]
Publication state
Published
Issued date
2009
Peer-reviewed
Oui
Volume
10
Number
5
Pages
432-446
Language
english
Abstract
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.
Keywords
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
Create date
23/11/2009 13:23
Last modification date
20/08/2019 12:24
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