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p23/Sba1p protects against Hsp90 inhibitors independently of its intrinsic chaperone activity

Toogun, Oyetunji A.
Suslova, Elena
Freeman, Brian C.
Published in Molecular and Cellular Biology. 2008, vol. 28, no. 10, p. 3446-56
Abstract The molecular chaperone Hsp90 assists a subset of cellular proteins and is essential in eukaryotes. A cohort of cochaperones contributes to and regulates the multicomponent Hsp90 machine. Unlike the biochemical activities of the cochaperone p23, its in vivo functions and the structure-function relationship remain poorly understood, even in the genetically tractable model organism Saccharomyces cerevisiae. The SBA1 gene that encodes the p23 ortholog in this species is not an essential gene. We found that in the absence of p23/Sba1p, yeast and mammalian cells are hypersensitive to Hsp90 inhibitors. This protective function of Sba1p depends on its abilities to bind Hsp90 and to block the Hsp90 ATPase and inhibitor binding. In contrast, the protective function of Sba1p does not require the Hsp90-independent molecular chaperone activity of Sba1p. The structure-function analysis suggests that Sba1p undergoes considerable structural rearrangements upon binding Hsp90 and that the large size of the p23/Sba1p-Hsp90 interaction surface facilitates maintenance of high affinity despite sequence divergence during evolution. The large interface may also contribute to preserving a protective function in an environment in which Hsp90 inhibitory compounds can be produced by various microorganisms.
Keywords Amino Acid SequenceAnimalsBase SequenceCells, CulturedDNA Primers/geneticsDNA, Fungal/geneticsGenes, FungalGenetic Complementation TestHSP90 Heat-Shock Proteins/antagonists & inhibitors/genetics/metabolismIntramolecular Oxidoreductases/deficiency/genetics/metabolismMiceModels, MolecularMolecular Chaperones/chemistry/genetics/metabolismMutagenesis, Site-DirectedPhenotypePoint MutationProtein BindingRecombinant Proteins/chemistry/genetics/metabolismSaccharomyces cerevisiae/genetics/metabolismSaccharomyces cerevisiae Proteins/antagonists & inhibitors/chemistry/genetics/metabolismSequence DeletionSequence Homology, Amino Acid
PMID: 18362168
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FORAFONOV, Fedor et al. p23/Sba1p protects against Hsp90 inhibitors independently of its intrinsic chaperone activity. In: Molecular and Cellular Biology, 2008, vol. 28, n° 10, p. 3446-56. doi: 10.1128/MCB.02246-07 https://archive-ouverte.unige.ch/unige:4476

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Deposited on : 2009-12-01

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