Document Detail

Transient interaction of Hsp90 with early unfolding intermediates of citrate synthase. Implications for heat shock in vivo.
MedLine Citation:
PMID:  7706269     Owner:  NLM     Status:  MEDLINE    
At normal temperatures, Hsp90 is one of the most abundant proteins in the cytosol of various eucaryotic cells. Upon heat shock, the level of Hsp90 is increased even more, suggesting that it is important for helping cells to survive under these conditions. However, studies so far have been almost exclusively concerned with the function of Hsp90 under non-stress conditions, and therefore only little is known about the role of Hsp90 during heat shock. As a model for heat shock in vitro, we have monitored the inactivation and subsequent aggregation of dimeric citrate synthase (CS) at elevated temperatures. Hsp90 effectively "stabilized" CS under conditions where the enzyme is normally inactivated and finally aggregates very rapidly. A kinetic dissection of the unfolding pathway of CS succeeded in revealing two intermediates which form and subsequently undergo irreversible aggregation reactions. Hsp90 apparently interacts transiently with these highly structured early unfolding intermediates. Binding and subsequent release of the intermediates favorably influences the kinetic partitioning between two competing processes, the further unfolding of CS and the productive refolding to the native state. As a consequence, CS is effectively stabilized in the presence of Hsp90. The significance of this interaction is especially evident in the suppression of aggregation, the major end result of thermal unfolding events in vivo and in vitro. These effects, which are ATP-independent, seem to be a general function of members of the Hsp90 family, since yeast and bovine Hsp90 as well as the Hsp90 homologue from Escherichia coli gave similar results. It seems likely that this function also reflects the role of Hsp90 under heat shock conditions in vivo. We therefore propose that members of the Hsp90 family convey thermotolerance by transiently binding to highly structured early unfolding intermediates, thereby preventing their irreversible aggregation and stabilizing the active species.
U Jakob; H Lilie; I Meyer; J Buchner
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  270     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1995 Mar 
Date Detail:
Created Date:  1995-05-10     Completed Date:  1995-05-10     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  7288-94     Citation Subset:  IM    
Institut für Biophysik & Physikalische Biochemie, Universität Regensburg, Federal Republic of Germany.
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MeSH Terms
Citrate (si)-Synthase / chemistry*,  metabolism*
Enzyme Activation
Enzyme Stability
Escherichia coli / metabolism
HSP90 Heat-Shock Proteins / chemistry*,  isolation & purification,  metabolism*
Macromolecular Substances
Pancreas / metabolism
Protein Denaturation
Protein Folding
Time Factors
Reg. No./Substance:
0/HSP90 Heat-Shock Proteins; 0/Macromolecular Substances; EC (si)-Synthase

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