Pharmacologic Shifting of a Balance between Protein Refolding and Degradation Mediated by Hsp90

The role of the abundant stress protein Hsp90 in protecting cells against stress-induced damage is not well understood. The recent discovery that a class of ansamycin antibiotics bind specifically to Hsp90 allowed us to address this problem from a new angle. We find that mammalian Hsp90, in cooperat...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1996-12, Vol.93 (25), p.14536-14541
Main Authors: Schneider, Christine, Sepp-Lorenzino, Laura, Nimmesgern, Elmar, Ouerfelli, Ouathek, Danishefsky, Samuel, Rosen, Neal, Hartl, F. Ulrich
Format: Article
Language:English
Subjects:
Animals
Antibodies
Biological Sciences
Cells
Cellular biology
Elution
Heat shock proteins
HSP90 Heat-Shock Proteins - metabolism
HSP90 Heat-Shock Proteins - pharmacology
Humans
Immunoblotting
Luciferases - drug effects
Luciferases - metabolism
Macrocyclic lactams
Mammals
Pharmacology
Potassium
Protein Folding
Protein refolding
Proteins
Signal Transduction
Ubiquitins
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Summary:The role of the abundant stress protein Hsp90 in protecting cells against stress-induced damage is not well understood. The recent discovery that a class of ansamycin antibiotics bind specifically to Hsp90 allowed us to address this problem from a new angle. We find that mammalian Hsp90, in cooperation with Hsp70, p60, and other factors, mediates the ATP-dependent refolding of heat-denatured proteins, such as firefly luciferase. Failure to refold results in proteolysis. The ansamycins inhibit refolding, both in vivo and in a cell extract, by preventing normal dissociation of Hsp90 from luciferase, causing its enhanced degradation. This mechanism also explains the ansamycin-induced proteolysis of several protooncogenic protein kinases, such as Raf-1, which interact with Hsp90. We propose that Hsp90 is part of a quality control system that facilitates protein refolding or degradation during recovery from stress. This function is used by a limited set of signal transduction molecules for their folding and regulation under nonstress conditions. The ansamycins shift the mode of Hsp90 from refolding to degradation, and this effect is probably amplified for specific Hsp90 substrates.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.93.25.14536