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Molecular and Cellular Biology, May 2008, p. 3446-3456, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.02246-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

p23/Sba1p Protects against Hsp90 Inhibitors Independently of Its Intrinsic Chaperone Activity{triangledown} ,{ddagger}

Fedor Forafonov,1 Oyetunji A. Toogun,2,{dagger} Iwona Grad,1 Elena Suslova,1 Brian C. Freeman,2 and Didier Picard1*

Département de Biologie Cellulaire, Université de Genève, Sciences III, 30 Quai Ernest-Ansermet, CH-1211 Genève 4, Switzerland,1 Department of Cell and Developmental Biology, University of Illinois, Urbana, Illinois 618012

Received 19 December 2007/ Returned for modification 30 January 2008/ Accepted 11 March 2008

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.

* Corresponding author. Mailing address: Département de Biologie Cellulaire, Université de Genève, Sciences III, CH-1211 Genève 4, Switzerland. Phone: 41 22 379 6813. Fax: 41 22 379 6928. E-mail: didier.picard{at}cellbio.unige.ch

{triangledown} Published ahead of print on 24 March 2008.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} Passed away on 3 August 2007.

Molecular and Cellular Biology, May 2008, p. 3446-3456, Vol. 28, No. 10
0270-7306/08/$08.00+0     doi:10.1128/MCB.02246-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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