In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 93, No. 25 ( 1996-12-10), p. 14536-14541
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.93.25.14536
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
1996
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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