The carboxy-terminal region of mammalian HSP90 is required for its dimerization and function in vivo.

Minami, Yoshiko; Kimura, Y; Kawasaki, Hiroshi; Suzuki, K; Yahara, Ichiro

doi:10.1128/mcb.14.2.1459

Cited by 144 publications

(129 citation statements)

References 20 publications

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“…This causes the displacement of ATP and functional arrest of the Hsp90 chaperone cycle (Stebbins et al, 1997;Whitesell and Lindquist, 2005). The middle domain is followed by a carboxy-terminal domain (CTD) which mediates dimerization and is less conserved in sequence (Harris et al, 2004;Minami et al, 1994). The five C-terminal residues (MEEVD motif) form a highly conserved TPR domain binding site that allows Hsp90 to interact with a number of co-chaperones containing TPR domains (Pearl and Prodromou, 2006;Young et al, 1998).…”

Section: Ii41122 the Hsp90 Chaperone Systemmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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Section: Ii41122 the Hsp90 Chaperone Systemmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…It is known that the carboxy-terminal portion of Hsp90 (540-724) is necessary and sufficient for dimerization. 10 A C-terminal fragment Hsp90 (177-724) was His6 tagged, whereas full-length Hsp90 (1-724) was untagged. When total cell-extract from cells expressing both the His-tagged C-terminal fragment of Hsp90 and untagged full-length Hsp90 were incubated with Ni-NTA resin, both proteins bound and were eluted together by imidazole (Fig.…”

Section: Analytical Ultracentrifugationmentioning

confidence: 99%

“…They are ubiquitinylated by C-terminus of Hsp interacting protein, an E3 ubiquitin ligase that also has a TPR domain that has been proposed to interact with the C-terminal peptide of either Hsp70 or Hsp90. 9 It is well established that Hsp90 is a dimer 10 and that Hsp70 is a monomer. 11 The oligomeric state of HOP, whether it is a dimer or a monomer, thus has important implications for the types of folding and degradation complexes that can be formed.…”

Section: Introductionmentioning

confidence: 99%

HOP is a monomer: Investigation of the oligomeric state of the co‐chaperone HOP

2009

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The co-chaperone Hsp70-Hsp90 organizing protein (HOP) plays a central role in protein folding in vivo, binding to both Hsp70 and Hsp90 and bringing them together in a functional complex. Reports in the literature concerning the oligomeric state of HOP have been inconsistent-is it a monomer, dimer, or higher order oligomer? Knowing the oligomeric state of HOP is important, because it places limits on the number and types of multiprotein complexes that can form during the folding cycle. Thus, the number of feasible models is simplified. Here, we explicitly investigate the oligomeric state of HOP using three complementary methods: gel filtration chromatography, sedimentation equilibrium analytical ultracentrifugation (AUC), and an in vivo coexpression assay. We find that HOP does not behave like a monomeric globular protein on gel filtration. Rather its behavior is consistent with it being either an elongated monomer or a dimer. We follow-up on these studies using sedimentation equilibrium AUC, which separates on the basis of molecular weight (MW), independent of shape. Sedimentation equilibrium AUC clearly shows that HOP is a monomer, with no indication of higher MW species. Finally, we use an in vivo coexpression assay that also supports the conclusion that HOP is a monomer.

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“…Interestingly, heterologous Hsp90 proteins from many species are able to replace Hsp82 and Hsc82 of the budding yeast. These include the two human cytosolic isoforms Hsp90␣ [13] and Hsp90␤ [14], Hsp90 from Trypanosoma cruzi [15], Drosophila [16], Caenorhabditis elegans and Candida albicans [17]. S. cerevisiae lends itself perfectly to explore the functional conservation of proteins from other species, to study their homologous and heterologous biochemical interactions, and to screen for novel species-specific drugs.…”

Section: Introductionmentioning

confidence: 99%

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

Wider

Péli-Gulli

Briand

et al. 2009

Molecular and Biochemical Parasitology

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Developing novel drugs against the unicellular parasite Plasmodium is complicated by the paucity of simple screening systems. Heat-shock proteins are an essential class of proteins for the parasite's cyclical life style between different cellular milieus and temperatures. The molecular chaperone Hsp90 assists a large variety of proteins, but its supporting functions for many proteins that are important for cancer have made it into a well-studied drug target. With a better understanding of the differences between Hsp90 of the malarial parasite and Hsp90 of its human host, new therapeutic options might become available. We have generated a set of isogenic strains of the budding yeast Saccharomyces cerevisiae where the essential yeast Hsp90 proteins have been replaced with either of the two human cytosolic isoforms Hsp90α or Hsp90β, or with Hsp90 from Plasmodium falciparum (Pf). All strains express large amounts of the Flag-tagged Hsp90 proteins and are viable. Even though the strain with Pf Hsp90 grows more poorly, it provides a tool to reconstitute additional aspects of the parasite Hsp90 complex and its interactions with substrates in yeast as a living test tube. Upon exposure of the set of Hsp90 test strains to the two Hsp90 inhibitors radicicol (Rd) and geldanamycin (GA), we found that the strain with Pf Hsp90 is relatively more sensitive to GA than to Rd compared to the strains with human Hsp90's. This indicates that this set of yeast strains could be used to screen for new Pf Hsp90 inhibitors with a wider therapeutic window

show abstract

The carboxy-terminal region of mammalian HSP90 is required for its dimerization and function in vivo.

Cited by 144 publications

References 20 publications

Firefly luciferase mutants as sensors of proteome stress

Firefly luciferase mutants as sensors of proteome stress

HOP is a monomer: Investigation of the oligomeric state of the co‐chaperone HOP

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

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