Reactive Cysteines of the 90-kDa Heat Shock Protein, Hsp90

Nardai, Gábor; Sass, Bálint; Eber, Jordan; Orosz, György; Csermely, Péter

doi:10.1006/abbi.2000.2075

Cited by 80 publications

(69 citation statements)

References 54 publications

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“…In the absence of GSH as an anti-oxidant, vicinal dithiol-specific SH reagent such as arsenite could react directly with the highly conserved Cys589/590 pair in Hsp90 impairing its chaperone activity [39]. Withdrawal of GSH and treatment with arsenite downregulated molecular chaperone Hsp90 at the transcriptional level and by ubiquitination, diminished its ability to bind cochaperone p50 Cdc37 , and destabilized Hsp90 client proteins Plk-1 and Cdk-4 in GCS-2 cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Glutathione protects cells against arsenite-induced toxicity

Habib

Shi

Lieberman

2007

Free Radical Biology and Medicine

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To understand the role of glutathione (GSH) in the protection of cells from arsenite toxicity, we studied the mechanism of apoptotic cell death in cells genetically unable to synthesize GSH (GCS-2 cells). Arsenite stimulated an increase in protein ubiquitination in GCS-2 cells while the wild type cells were unaffected. Arsenite treatment increased lipid peroxidation and induced ubiquitination of molecular chaperone Hsp90 and impaired its ability to bind cochaperone p50 and client proteins Plk-1 and Cdk-4 in GCS-2 cells. Treatment with arsenite also partially inhibited proteasome activity in GCS-2 cells. In these cells stably transfected with GFP u (a reporter consisting of a short degron fused to the COOH-terminus of GFP), intracellular fluorescence increased, suggesting the accumulation of GFP aggregates. GCS-2 cells underwent apoptosis accompanied by release of cytochrome C into the cytoplasm. Taken together, these data suggest that a possible mechanism of arsenite-induced apoptosis is the accumulation of ubiquitinated proteins and impairment of the protein degradative pathway. Further, protection from arsenite-induced ubiquitination is mediated by GSH and to a lesser extent by available reducing equivalents in the cells.

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Section: Discussionmentioning

confidence: 99%

Glutathione protects cells against arsenite-induced toxicity

Habib

Shi

Lieberman

2007

Free Radical Biology and Medicine

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“…Under conditions of oxidative stress, the four thiolates form two intramolecular disulfide bonds which cause release of Zn, and subsequent dimerization of oxidized monomers, which effectuates full activation of Hsp33's function as a chaperone [147][148][149]. Similarly, mammalian Hsp25, 60, 70, and 90 also have redox active cysteine residues, and their oxidation has been linked to the modification of various chaperone functions in conditions of oxidative stress [150][151][152][153]. Various cysteine oxidations have been linked to Hsp activation that include nitrosylation, glutathionylation, and disulfide formation [151,152,154,155] (Figure 2, box 3).…”

Section: Regulation Of Molecular Adaptors and Chaperonesmentioning

confidence: 99%

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

Janssen–Heininger¹,

Mossman²,

Heintz³

et al. 2008

Free Radical Biology and Medicine

697

652

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“…19). They have also been previously identified as reactive cysteines in rat Hsp90 (20). We have built a model of the Hsp90␣ region spanning the mapped cysteines (Fig.…”

Section: Identification Of S-nitrosylated Cysteine Residue(s) Of Hsp9mentioning

confidence: 99%

S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities

Martínez‐Ruiz

Villanueva²,

Orduña³

et al. 2005

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

281

221

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Nitric oxide is implicated in a variety of signaling pathways in different systems, notably in endothelial cells. Some of its effects can be exerted through covalent modifications of proteins and, among these modifications, increasing attention is being paid to S-nitrosylation as a signaling mechanism. In this work, we show by a variety of methods (ozone chemiluminescence, biotin switch, and mass spectrometry) that the molecular chaperone Hsp90 is a target of S-nitrosylation and identify a susceptible cysteine residue in the region of the C-terminal domain that interacts with endothelial nitric oxide synthase (eNOS). We also show that the modification occurs in endothelial cells when they are treated with S-nitroso-L-cysteine and when they are exposed to eNOS activators. Hsp90 ATPase activity and its positive effect on eNOS activity are both inhibited by S-nitrosylation. Together, these data suggest that S-nitrosylation may functionally regulate the general activities of Hsp90 and provide a feedback mechanism for limiting eNOS activation.atherosclerosis ͉ nitrosation ͉ vascular wall ͉ chaperone R ecent years have witnessed an increasing interest in the roles of nitric oxide (NO) in signal transduction pathways other than its activation of the cGMP pathway. Many of these roles rely on NO's ability to alter protein function through posttranslational modifications. Among these modifications, S-nitrosylation has emerged as a potential and fundamental regulator of protein function. S-nitrosylation is a covalent modification of thiol groups by formation of a thionitrite (-S-NϭO) group, facilitated by the formation of higher nitrogen oxides (1, 2). To date, several dozens of proteins have been shown to become S-nitrosylated and, in many cases, this modification was accompanied by altered function (see table S1 of ref. 1 for review).Nitric oxide, synthesized in the endothelium by endothelial nitric oxide synthase (eNOS), plays crucial roles in the vascular wall, including the maintenance of vascular tone. The possibility that NO might modify eNOS, or elements of the complex system involved in its activation, is an attractive hypothesis, suggesting a potential autoregulatory feedback mechanism. The eNOS enzyme is regulated by several posttranslational modifications including myristoylation, palmitoylation, and phosphorylation (3). This enzyme is also tightly regulated by specific interactions with inhibitory proteins such as caveolin-1 and by positive modulation by the scaffolding protein Hsp90. These interactions have been described in detail, and a relatively complete picture is beginning to emerge (4).We have previously used a proteomic approach to identify several proteins that were S-nitrosylated after exposure of vascular endothelial cells to the physiological nitrosothiol, Snitroso-L-cysteine (CSNO) (5). Further work led to the identification of Hsp90 as a protein susceptible to S-nitrosylation. This chaperone protein, known for its functions in protein folding, degradation, and scaffolding, has attracted renewed ...

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Reactive Cysteines of the 90-kDa Heat Shock Protein, Hsp90

Cited by 80 publications

References 54 publications

Glutathione protects cells against arsenite-induced toxicity

Glutathione protects cells against arsenite-induced toxicity

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities

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