The Hsp90 mosaic: a picture emerges

Mayer, Mathias; Prodromou, Chrisostomos; Frydman, Judith

doi:10.1038/nsmb0109-2

Cited by 39 publications

(38 citation statements)

References 22 publications

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“…A detailed mechanism of resistance to radicicol was recently determined for the fungus Humicola fuscoatra, which produces radicicol 5 . The Hsp90 from the fungus contains amino acid substitutions that reduce radicicol affinity but do not affect ATPase activity.…”

Section: Discussionmentioning

confidence: 99%

Thermodynamics of radicicol binding to human Hsp90 alpha and beta isoforms

Zubrienė¹,

Gutkowska²,

Matulienė³

et al. 2010

Biophysical Chemistry

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Radicicol is a natural antibiotic that specifically inhibits chaperone Hsp90 activity and binds to its active site with nanomolar affinity. Radicicol has been widely used as a lead compound to generate synthetic analogs with reduced toxicity and increased stability that could be employed clinically. Here we present a detailed thermodynamic description of radicicol binding to human Hsp90 and yeast Hsc82 studied by isothermal titration calorimetry and thermal shift assay.Titrations as a function of pH showed a linked protonation event upon radicicol binding. The intrinsic binding constant and the thermodynamic parameters (including the enthalpy, entropy, and heat capacity) were determined for yeast Hsc82, and human alpha and beta Hsp90. Recent experimental evidence in literature shows that yeast Hsc82 has significant differences from human Hsp90 isozymes. Here we support this by demonstrating differences in radicicol binding thermodynamics to these proteins. The intrinsic enthalpy of radicicol binding to Hsc82 was -46.7 kJ/mol, to Hsp90alpha -70.7 kJ/mol, and to Hsp90beta was -66.8 kJ/mol. The enthalpies of binding were significantly different, while the intrinsic dissociation constants were quite similar,

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Section: Discussionmentioning

confidence: 99%

Thermodynamics of radicicol binding to human Hsp90 alpha and beta isoforms

Zubrienė¹,

Gutkowska²,

Matulienė³

et al. 2010

Biophysical Chemistry

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“…Functionally, the binding of ATP to the amino-terminal domain of Hsp90 regulates a cycle of conformational changes responsible for the chaperone activity (23). Interestingly, the two tyrosine residues located in the amino-terminal domain, Tyr38 and Tyr61 in Hsp90α and Tyr33 and Tyr56 in Hsp90β, are required for the intrinsic ATPase activity of the chaperone.…”

Section: Resultsmentioning

confidence: 99%

Nitration of Hsp90 induces cell death

Franco

Ye²,

Refakis

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

121

157

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Oxidative stress is a widely recognized cause of cell death associated with neurodegeneration, inflammation, and aging. Tyrosine nitration in these conditions has been reported extensively, but whether tyrosine nitration is a marker or plays a role in the cell-death processes was unknown. Here, we show that nitration of a single tyrosine residue on a small proportion of 90-kDa heat-shock protein (Hsp90), is sufficient to induce motor neuron death by the P2X7 receptor-dependent activation of the Fas pathway. Nitrotyrosine at position 33 or 56 stimulates a toxic gain of function that turns Hsp90 into a toxic protein. Using an antibody that recognizes the nitrated Hsp90, we found immunoreactivity in motor neurons of patients with amyotrophic lateral sclerosis, in an animal model of amyotrophic lateral sclerosis, and after experimental spinal cord injury. Our findings reveal that cell death can be triggered by nitration of a single protein and highlight nitrated Hsp90 as a potential target for the development of effective therapies for a large number of pathologies.apoptosis | peroxynitrite | PC12 cells

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“…Its activity depends on ATP binding and a hydrolysis cycle during which Hsp90 undergoes large conformational changes. [8][9][10] Hsp90 is known to regulate signal transduction via modulation of signaling molecules, such as protein kinases and eNOS. Indeed, after stimulation of ECs with agonists known to stimulate NO production, Hsp90 associates with eNOS, and it has been suggested that Hsp90 acts as a scaffold to recruit the serine/ threonine kinase AKT, which leads to increased eNOS activity.…”

mentioning

confidence: 99%

Modulation of the Cochaperone AHA1 Regulates Heat-Shock Protein 90 and Endothelial NO Synthase Activation by Vascular Endothelial Growth Factor

Desjardins

Delisle

Gratton

2012

ATVB

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Objective-Vascular endothelial growth factor (VEGF) signaling to endothelial NO synthase (eNOS) plays a central role in angiogenesis. In endothelial cells (ECs), heat-shock protein 90 (Hsp90) is also a regulator of eNOS activity. Our study is designed to determine whether modulation of the activator of Hsp90 ATPase 1 (AHA1) regulates the function of Hsp90 in ECs. Methods and Results-We show that eNOS phosphorylation on Ser-1179 after VEGF stimulation is significantly reduced in ECs transfected with a small interfering RNA against AHA1. Accordingly, VEGF-stimulated NO production, endothelial permeability, cell migration, and EC invasion in Matrigel implants in mice are reduced in small interfering RNA against AHA1-treated conditions. Furthermore, the induction of eNOS association with Hsp90 after VEGF stimulation is decreased in AHA1-downregulated cells. We also demonstrate that modulation of Hsp90 activity by AHA1 regulates phosphorylation of Hsp90 on Tyr-300. Interestingly, the association of AHA1 with Hsp90 is increased after c-Src-mediated phosphorylation of Hsp90 on Tyr-300. Finally, we show that overexpression of AHA1 in ECs promotes association of eNOS and Hsp90, phosphorylation of Ser-1179 of eNOS, increases NO production, and cell migration. Conclusion-These

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The Hsp90 mosaic: a picture emerges

Abstract: Hsp90s, molecular chaperones critically involved in many essential cellular processes, were the focus of a recent international conference held in Seeon, Germany. The scope of the conference ranged from structural and mechanistic insights all the way to medical applications.

Cited by 39 publications

References 22 publications

Thermodynamics of radicicol binding to human Hsp90 alpha and beta isoforms

Thermodynamics of radicicol binding to human Hsp90 alpha and beta isoforms

Nitration of Hsp90 induces cell death

Modulation of the Cochaperone AHA1 Regulates Heat-Shock Protein 90 and Endothelial NO Synthase Activation by Vascular Endothelial Growth Factor

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