Protein‐sulfenic acid stabilization and function in enzyme catalysis and gene regulation

Claiborne, Al; Miller, Holly; Parsonage, Derek; Ross, R. Paul

doi:10.1096/fasebj.7.15.8262333

Cited by 245 publications

(189 citation statements)

References 34 publications

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“…This idea is supported by the propensity of these species to self-stabilize by sulfenyl-amide formation, dimerize to the thiosulfinate, react with oxygen to sulfinic or sulfonic acid, form disulfide bonds, or be reduced by vicinal or low-molecular-weight thiols. Despite their reactivity, it is now clear that some sulfenic acids are more stable, and these can be identified in proteins under physiological conditions (21,(25)(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

Widespread sulfenic acid formation in tissues in response to hydrogen peroxide

Saurin

Neubert

Brennan

et al. 2004

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

271

277

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A principal product of the reaction between a protein cysteinyl thiol and hydrogen peroxide is a protein sulfenic acid. Because protein sulfenic acid formation is reversible, it provides a mechanism whereby changes in cellular hydrogen peroxide concentration may directly control protein function. We have developed methods for the detection and purification of proteins oxidized in this way. The methodology is based on the arsenite-specific reduction of protein sulfenic acid under denaturing conditions and their subsequent labeling with biotin-maleimide. Arsenite-dependent signal generation was fully blocked by pretreatment with dimedone, consistent with its reactivity with sulfenic acids to form a covalent adduct that is nonreducible by thiols. The biotin tag facilitates the detection of protein sulfenic acids on Western blots probed with streptavidin-horseradish peroxidase and also their purification by streptavidin-agarose. We have characterized protein sulfenic acid formation in isolated hearts subjected to hydrogen peroxide treatment. We have also purified and identified a number of the proteins that are oxidized in this way by using a proteomic approach. Using Western immunoblotting we demonstrated that a highly significant proportion of some individual proteins (68% of total in one case) form the sulfenic derivative. We conclude that protein sulfenic acids are widespread physiologically relevant posttranslational oxidative modifications that can be detected at basal levels in healthy tissue, and are elevated in response to hydrogen peroxide. These approaches may find widespread utility in the study of oxidative stress, particularly because hydrogen peroxide is used extensively in models of disease or redox signaling.heart ͉ oxidative stress ͉ myocardium ͉ redox signaling

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Section: Discussionmentioning

confidence: 99%

Widespread sulfenic acid formation in tissues in response to hydrogen peroxide

Saurin

Neubert

Brennan

et al. 2004

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

271

277

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“…This result suggests the existence of an Hsp33 oxidation intermediate and not of a dead-end product. We were surprised to discover this intermediate, because H 2 O 2 is thought to oxidize cysteine thiols to highly reactive sulfenic acids, which very rapidly react with nearby cysteines to form disulfide bonds 15,16 . Thus, the detection of a singly oxidized cysteine suggests that accessibility or reactivity of the nearby cysteine might limit the oxidation process at 30 °C.…”

Section: Hsp33's Activation Requires H 2 O 2 and Elevated Temperaturesmentioning

confidence: 99%

The redox-switch domain of Hsp33 functions as dual stress sensor

Ilbert

Horst

Ahrens

et al. 2007

Nat Struct Mol Biol

170

207

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The redox-regulated chaperone Hsp33 is specifically activated upon exposure of cells to peroxide stress at elevated temperatures. Here we show that Hsp33 harbors two interdependent stress-sensing regions located in the C-terminal redox-switch domain of Hsp33: a zinc center sensing peroxide stress conditions and an adjacent linker region responding to unfolding conditions. Neither of these sensors works sufficiently in the absence of the other, making the simultaneous presence of both stress conditions a necessary requirement for Hsp33's full activation. Upon activation, Hsp33's redox-switch domain adopts a natively unfolded conformation, thereby exposing hydrophobic surfaces in its N-terminal substrate-binding domain. The specific activation of Hsp33 by the oxidative unfolding of its redox-switch domain makes this chaperone optimally suited to quickly respond to oxidative stress conditions that lead to protein unfolding.Reactive oxygen species develop as unavoidable consequences of aerobic life. Their oxidizing effects on most cellular macromolecules can be deleterious to cells and organisms 1 . Cells have developed effective antioxidant systems to counteract this hazard (for review, see ref. 2 ). Disruption of the fine balance between oxidants and antioxidants, however, leads to the accumulation of reactive oxygen species and to a condition termed oxidative stress 3 . Oxidative stress conditions have been shown to develop in, and may even cause, numerous physiological and pathological conditions, such as aging, heart disease, diabetes and neurodegenerative diseases 4 .

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“…The last have been generated by the oxidation of coordinated thiolate ligands (30), though we are unaware that such oxidation products, including disulfides, can act as metal ligands in a biological zinc complex. Sulfenic acid derivatives of cysteine, however, have been identified in a few enzymes either as stable or functional residues (31). Their stabilization requires the absence of other vicinal thiols.…”

Section: Biochemistry: Maret and Valleementioning

confidence: 99%

Thiolate ligands in metallothionein confer redox activity on zinc clusters

Maret

Vallée

1998

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

531

319

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We postulate a novel and general mechanism in which the redox-active sulfur donor group of cyst(e)ine confers oxidoreductive characteristics on stable zinc sites in proteins. Thus, the present, an earlier, and accompanying manuscripts Metallothionein (MT) is a unique metalloprotein in which cysteine constitutes one-third of its amino acids and histidine and aromatic amino acids all are completely absent. All 20 cysteines bind seven zinc atoms such that each metal atom has a complement of four cysteine ligands. It is important to emphasize that the by now well known multinuclear cluster network, identified by both x-ray diffraction and NMR spectroscopy only less than a decade ago (1,2), shows the exceptional structural arrangement that was hitherto unknown in zinc/sulfur chemistry and has thus far been encountered solely in biological material such as MT. The zinc/cysteinyl interactions in the two clusters are of two different types: they are either bridging or terminal cysteine thiolates. In the ␤-domain cluster, three bridging and six terminal cysteine thiolates provide a coordination environment that is formally identical for each of the three zinc atoms. In the ␣-domain cluster, there are two different zinc sites; two of them have one terminal ligand and three bridging ligands, respectively, while the other two have two terminal and two bridging ligands.We have performed and advocated experiments to relate the structure of MT to its possible function(s) on the basis of the nature of zinc coordination in MT (3-5). We have suggested that the characteristics of the cluster motif might be the key to the mode of cellular zinc distribution (6). MT binds zinc with high thermodynamic stability [K d ϭ 1.4 ϫ 10 Ϫ13 M for human MT at pH 7.0 (7)] while simultaneously providing a mechanism for kinetic lability whereby zinc can be released at rates that are orders of magnitude greater than those observed for zinc metalloenzymes. Zinc, as well as cadmium, is known to undergo rapid inter-and intracluster exchange (8, 9).MT apparently binds zinc with higher affinity than do many other proteins. For MT to serve as a source for the distribution of zinc, mechanisms would be required that could regulate the binding and release of the metal. It has been shown that an interaction of MT with glutathione disulfide (GSSG) or other biological disulfides releases zinc (10, 11) and that the combination of reduced glutathione (GSH) and GSSG enhances transfer of zinc from MT to an apoenzyme (12). This has led us to infer that the reactivity and redox behavior of the sulfur ligands in the MT clusters are crucial for the dynamic state of zinc. We proposed that the zinc-sulfur cluster chemistry might be sensitive to changes of the cellular redox state and that oxidizing conditions induce the transfer of zinc from its binding sites in MT to those of lower affinity in other proteins.We here provide additional support for this concept and show that a number of compounds, including some of potential biological importance, can oxidize the ...

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Protein‐sulfenic acid stabilization and function in enzyme catalysis and gene regulation

Cited by 245 publications

References 34 publications

Widespread sulfenic acid formation in tissues in response to hydrogen peroxide

Widespread sulfenic acid formation in tissues in response to hydrogen peroxide

The redox-switch domain of Hsp33 functions as dual stress sensor

Thiolate ligands in metallothionein confer redox activity on zinc clusters

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