Abstract
The chaperone cycle of heat shock protein-90 (Hsp90) involves progression through defined complexes with different cochaperones. It is still enigmatic how the exchange of cochaperones is regulated. The first cochaperone entering the cycle is the Hsp90 ATPase inhibitor Sti1 (Hop in human), which later is replaced by a prolyl isomerase (PPIase) and p23. We found, unexpectedly, that one Sti1 molecule is sufficient to completely inhibit the ATPase of the Hsp90 dimer. Upon addition of a PPIase cochaperone to the Hsp90-Sti1 complex, an asymmetric ternary complex is preferentially formed. This PPIase-Hsp90-Sti1 intermediate is important for the progression of the cycle. To expel the bound Sti1, the concerted action of ATP and p23 is required. This mechanism, which is strictly conserved between the yeast and human Hsp90 systems, presents an example of how, in a cyclic process, directionality of assembly and disassembly of protein complexes can be achieved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenylyl Imidodiphosphate / metabolism
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Cyclophilins / metabolism
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HSP90 Heat-Shock Proteins / antagonists & inhibitors
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HSP90 Heat-Shock Proteins / chemistry
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HSP90 Heat-Shock Proteins / physiology*
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Heat-Shock Proteins / metabolism
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Heat-Shock Proteins / physiology
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Heat-Shock Response / physiology*
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Homeodomain Proteins / metabolism
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Homeodomain Proteins / physiology
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / physiology
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Models, Biological
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Peptidyl-Prolyl Isomerase F
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Saccharomyces cerevisiae Proteins / metabolism
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Saccharomyces cerevisiae Proteins / physiology
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Tumor Suppressor Proteins / metabolism
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Tumor Suppressor Proteins / physiology
Substances
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Peptidyl-Prolyl Isomerase F
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HOPX protein, human
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HSP90 Heat-Shock Proteins
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Heat-Shock Proteins
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Homeodomain Proteins
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Intracellular Signaling Peptides and Proteins
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STI1 protein, S cerevisiae
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Saccharomyces cerevisiae Proteins
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Tumor Suppressor Proteins
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aryl hydrocarbon receptor-interacting protein
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Adenylyl Imidodiphosphate
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Cyclophilins