The Co-chaperone p23 Arrests the Hsp90 ATPase Cycle to Trap Client Proteins

McLaughlin, Stephen H.; Sobott, Frank; Yao, Zhongping; Zhang, Wei; Nielsen, Peter R.; Grossmann, J. Günter; Laue, Ernest D.; Robinson, Carol V.; Jackson, Sophie

doi:10.1016/j.jmb.2005.11.085

Cited by 178 publications

(173 citation statements)

References 58 publications

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“…As determined by kinetic studies, p23 uses a mixed inhibition mechanism, and the binding of p23 increases the K m for AMPPNP binding to Hsp90. If the p23:Hsp90 complex cannot bind AMPPNP once it is formed, the increase in Hsp90's affinity for AMPPNP in the presence of p23 would result from the relatively higher affinity of p23 for the AMPPNP-bound Hsp90 rather than Hsp90 alone (McLaughlin et al, 2006). The motion of the lid over the nucleotide binding pocket when p23 binds (Figure 9) blocks access to the nucleotide binding pocket supporting this model.…”

Section: P23 Arrests the Atpase Cycle Of Hsp90mentioning

confidence: 83%

“…The complex promotes or stabilizes the closed conformation and leads to the inhibition of the ATPase activity with inhibition observed for both yHsp90 and hHsp90 (McLaughlin et al, 2002;McLaughlin et al, 2006;Richter et al, 2004;Siligardi et al, 2004). Biochemical data demonstrate that p23 preferentially binds to the NTD dimerized state (McLaughlin et al, 2006;Prodromou et al, 2000;Richter et al, 2004), and a crystal structure of the full-length yeast protein bound to residues 1-134 of p23 (the complete protein is 160 residues). confirms that p23 stabilizes the closed AMPPNP-bound form of Hsp90 (Figure 9) )‥ The affinity of Hsp90 for p23 can be tuned with Hsp90 mutants that either increase or decrease NTD dimerization.…”

Section: P23 Arrests the Atpase Cycle Of Hsp90mentioning

confidence: 99%

“…In yeast, Δ8-Hsp90 (increased ATPase activity) hydrolyzes ATP even at saturating levels of bound p23 (Richter et al, 2004). Complete inhibition of hHsp90's ATPase was observed in the presence of p23 but the binding of other co-chaperones may displace p23 and overcome inhibition (McLaughlin et al, 2006). In the absence of other co-chaperones stochastic fluctuations in the p23:Hsp90 complex, as observed in lysates (Johnson & Toft, 1995), could allow hydrolysis to occur and the chaperone cycle to continue‥ Also, the half-life (T 1/2 ) of the human p23:Hsp90 complex is 40 seconds at 37°C whereas the T 1/2 of hydrolysis is 7 minutes (McLaughlin et al, 2006) providing additional corroboration for the dynamic nature of the p23:Hsp90 complex.…”

Section: P23 Arrests the Atpase Cycle Of Hsp90mentioning

confidence: 99%

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Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

279

262

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The molecular chaperone Hsp90 is an essential eukaryotic protein that makes up 1-2% of all cytosolic proteins. Hsp90 is vital for the maturation and maintenance of a wide variety of substrate proteins largely involved in signaling and regulatory processes. Many of these substrates have also been implicated in cancer and other diseases making Hsp90 an attractive target for therapeutics. Hsp90 is a highly dynamic and flexible molecule that can adapt its conformation to the wide variety of substrate proteins with which it acts. Large conformational rearrangements are also required for the activation of these client proteins. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis shifts the equilibrium between a pre-existing set of conformational states in an organismdependent manner. In vivo Hsp90 functions as part of larger heterocomplexes. The binding partners of Hsp90, co-chaperones, assist in the recruitment and activation of substrates, and many co-chaperones further regulate the conformational dynamics of Hsp90 by shifting the conformational equilibrium towards a particular state. Studies have also suggested alternative mechanisms for the regulation of Hsp90's conformation. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90 and the role that nucleotide, co-chaperones, post-translational modification and clients play in regulating Hsp90's conformation. We also discuss the effects of current Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics.

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Section: P23 Arrests the Atpase Cycle Of Hsp90mentioning

confidence: 83%

Section: P23 Arrests the Atpase Cycle Of Hsp90mentioning

confidence: 99%

Section: P23 Arrests the Atpase Cycle Of Hsp90mentioning

confidence: 99%

See 1 more Smart Citation

Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

279

262

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“…Cochaperones such as HOP and p23 inhibit Hsp90's ATPase activity and are likely to be involved in client loading or the formation of a Hsp90-client substrate complex (McLaughlin et al, 2006;Schmid et al, 2012;Southworth and Agard, 2011;Young and Hartl, 2000). The co-chaperone AHA1 (Activator of Hsp90 ATPase homologue 1) stimulates the Hsp90 conformational cycle by enhancing the ATPase activity and permitting the substrate release for the next maturation step (Meyer et al, 2004;Panaretou et al, 2002).…”

Section: Ii41122 the Hsp90 Chaperone Systemmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

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“…The co-chaperone AHSA1 binds exclusively to the ATP-bound HSP90 and stimulates ATP hydrolysis, and this interaction is thought to influence client protein activation (9 -12). In addition, several studies have shown the co-chaperone p23 to preferentially interact with the ATP-bound HSP90, inhibiting ATP hydrolysis (7,(13)(14)(15). Inhibition of ATP binding and hydrolysis by the pharmacological inhibitor geldanamycin is generally observed to disrupt HSP90 interactions with co-chaperones and client proteins; however, some exceptions exist where geldanamycin has no effect or stabilizes interactions (16,17).…”

mentioning

confidence: 99%

A Proteomic Investigation of Ligand-dependent HSP90 Complexes Reveals CHORDC1 as a Novel ADP-dependent HSP90-interacting Protein

Gano

Simon

2010

Molecular & Cellular Proteomics

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Structural studies of the chaperone HSP90 have revealed that nucleotide and drug ligands induce several distinct conformational states; however, little is known how these conformations affect interactions with co-chaperones and client proteins. Here we use tandem affinity purification and LC-MS/MS to investigate the proteome-wide effects of ATP, ADP, and geldanamycin on the constituents of the human HSP90 interactome. We identified 52 known and novel components of HSP90 complexes that are regulated by these ligands, including several co-chaperones. Interestingly, our results also show that geldanamycin treatment causes HSP90 complexes to become significantly enriched for core transcription machinery, suggesting that HSP90 inhibition may have broad based effects on transcription and RNA processing. We further characterized a novel ADP-dependent HSP90 interaction with the cysteine-and histidine-rich domain (CHORD)-containing protein CHORDC1. We show that this interaction is stimulated by high ADP:ATP ratios in cell lysates and in vitro with purified recombinant proteins. Furthermore, we demonstrate that this interaction is dependent upon the ability of HSP90 to bind nucleotides and requires the presence of a linker region between the CHORD domains in CHORDC1. Together these findings suggest that the HSP90 interactome is dynamic with respect to nucleotide and drug ligands and that pharmacological inhibition of HSP90 may stimulate the formation of specific complexes. Molecular & Cellular Proteomics 9:255-270, 2010.

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The Co-chaperone p23 Arrests the Hsp90 ATPase Cycle to Trap Client Proteins

Cited by 178 publications

References 58 publications

Conformational dynamics of the molecular chaperone Hsp90

Conformational dynamics of the molecular chaperone Hsp90

Firefly luciferase mutants as sensors of proteome stress

A Proteomic Investigation of Ligand-dependent HSP90 Complexes Reveals CHORDC1 as a Novel ADP-dependent HSP90-interacting Protein

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