ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone invivo

Panaretou, Barry; Prodromou, Chrisostomos; Roe, S. Mark; O’Brien, Rita Cruise; Ladbury, John E.; Piper, Peter W.; Pearl, Laurence H.

doi:10.1093/emboj/17.16.4829

Cited by 682 publications

(703 citation statements)

References 68 publications

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“…The additional conformational change in the HSP90\CDDP complex by ATP may cause a slight recovery of the chaperone activity or dissociation of HSP90 from CDDP. (ii) It has been shown that complete HSP90 possesses a chaperone activity in i o dependent on ATP binding and ATP hydrolysis [21,22]. The CDDP binding site was located in the COOH-terminal domain of HSP90 (this study).…”

Section: Discussionmentioning

confidence: 61%

“…The chaperone activity of HSP90 is inhibited by ansamycin antibiotics (GA) [18]. Recently, it has been published that the in i o function of HSP90 is dependent on ATP binding and ATP hydrolysis [21,22]. Furthermore, an important result has been reported that HSP90 acts as a capacitor for morphological evolution [41].…”

Section: Discussionmentioning

confidence: 99%

“…On the contrary, the COOH-terminal fragment binds to partially folded proteins in an ATP-independent manner. Recently, it has been reported that the in i o function of HSP90 is dependent on ATP binding and ATP hydrolysis [21,22]. Thus, HSP90 contains two independent chaperone sites ; both NH # -and COOH-domains suppress protein aggregation, with differential specificity.…”

Section: Introductionmentioning

confidence: 99%

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A novel chaperone-activity-reducing mechanism of the 90-kDa molecular chaperone HSP90

Itoh

Ogura

Komatsuda

et al. 1999

Biochemical Journal

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The 90-kDa heat shock protein (HSP90) acts as a specific molecular chaperone in the folding and regulates a wide range of associated proteins such as steroid hormone receptors. It is known that HSP90 possesses two different chaperone sites, both in the N-and C-domains, and that the chaperone activity of HSP90 is blocked by binding of geldanamycin (GA) to the Ndomain, the same as the ATP-binding site. Here we show that Cisplatin [cis-diamminedichloroplatinum (II), CDDP], an antineoplastic agent, associates with HSP90 and reduces its chaperone activity. In order to analyse the binding proteins, bovine brain cytosols were applied to a CDDP-affinity column and binding proteins were eluted by CDDP. In the elutants, only 90-kDa protein bands were detected on SDS\PAGE, and the protein was cross-reacted with the anti-HSP90 antibody on immunoblotting. No protein bands were detected in the elutants

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A novel chaperone-activity-reducing mechanism of the 90-kDa molecular chaperone HSP90

Itoh

Ogura

Komatsuda

et al. 1999

Biochemical Journal

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“…All strains are derived from strain pp30#10 [21] [22], we deleted the gene encoding the export pump Pdr5 by using homologous recombination to replace the coding region with the loxP-LEU2-loxP cassette from plasmid pUG73 [23]. This generated yeast strain DP533.…”

Section: Yeast Strainsmentioning

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

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“…Additionally, biochemical studies suggest that transitory interactions between two N-terminal domains of the Hsp90 homodimer occur in an ATP-dependent manner, and this provides the mechanistic basis for an ATPase-driven molecular clamp [13]. Mutations in this region that impair the ability of Hsp90 to either bind or hydrolyze ATP eliminate its chaperone activity [14]. The discovery that the antibiotics, radicicol and geldanamycin, inhibit the Hsp90-dependent activation of numerous regulatory and signal transduction proteins by occupying their ATP-binding sites was a revelation in antitumor research [15].…”

mentioning

confidence: 99%

Hsp90—From signal transduction to cell transformation

Brown

Zhu

Schmidt

et al. 2007

Biochemical and Biophysical Research Communications

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The molecular chaperone, Hsp90, facilitates the maturation and/or activation of over 100 'client proteins' involved in signal transduction and transcriptional regulation. Largely an enigma among the families of heat shock proteins, Hsp90 is central to processes broadly ranging from cell cycle regulation to cellular transformation. Here we review the contemporary body of knowledge regarding the biochemical mechanisms of Hsp90 and update the most current paradigms defining its involvement in both normal and pathological cell physiology. KeywordsHsp90; heat shock protein; molecular chaperone; ATPase; genetic capacitor Hsp90 defines a family of molecular chaperones that are highly conserved from prokaryotes to eukaryotes [1][2][3][4][5]. Nonessential for normal growth in most bacteria, Hsp90 is abundantly expressed in higher eukaryotes where it has been shown to be necessary for viability [6,7]. It functions as a homodimer that associates with co-chaperones to catalyze the maturation and/ or activation of over 100 substrate proteins that are known to be involved in cell regulatory pathways [5]. These 'client proteins' include protein kinases, nuclear hormone receptors, transcription factors, and an array of other essential proteins [8]. While much is known regarding the ATPase-driven conformational cycling of Hsp90, the precise physical effects imparted by this chaperone that serve to activate its substrates are still poorly understood [5]. Hsp90 architectureThree highly conserved domains comprise the structure of Hsp90. These include the N-terminal domain, responsible for ATP-binding, a proteolytically resistant core domain, and the Cterminal domain that facilitates homodimerization (Fig. 1a) [9]. In eukaryotes, a more variable charged region links the N-terminal domain to the core domain. The length and composition of this linker region is highly divergent among organisms [10]. As no atomic resolution structure for full-length Hsp90 is yet available, the most thorough structural analyses for Hsp90, to date, have been based on crystallographic studies of its individual domains.A mechanistic understanding of Hsp90 was nebulous until partial sequence homology was recognized between its N-terminal domain and two types of ATP-dependent proteins. These

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ATP binding and hydrolysis are essential to the function of the Hsp90 molecular chaperone invivo

Cited by 682 publications

References 68 publications

A novel chaperone-activity-reducing mechanism of the 90-kDa molecular chaperone HSP90

A novel chaperone-activity-reducing mechanism of the 90-kDa molecular chaperone HSP90

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

Hsp90—From signal transduction to cell transformation

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