Thiol-Based Regulatory Switches

Paget, Mark S. B.; Buttner, Mark J.

doi:10.1146/annurev.genet.37.110801.142538

Cited by 263 publications

(224 citation statements)

References 110 publications

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“…For example, sulfenic acid modification (SOH) (hydroxylation) of a single allosteric cysteine has been shown to elicit effects on structure and function that are distinct from those elicited by mixed disulfide (glutathionylation) [32]. Cysteines are thus believed to serve as molecular switches, capable of processing different redox-based signals into distinct functional responses [36][37][38].…”

Section: Oxidizable Amino Acids: Reactive Cysteines As Redox Targetsmentioning

confidence: 99%

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

Janssen–Heininger¹,

Mossman²,

Heintz³

et al. 2008

Free Radical Biology and Medicine

687

646

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Section: Oxidizable Amino Acids: Reactive Cysteines As Redox Targetsmentioning

confidence: 99%

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

Janssen–Heininger¹,

Mossman²,

Heintz³

et al. 2008

Free Radical Biology and Medicine

687

646

View full text Add to dashboard Cite

“…Increased GSSG levels can modify protein function via reaction with free cysteine -SH groups to form intramolecular or intermolecular disulfides, or protein-mixed disulfides [1,2,3]. Although GSH is considered the main target of diamide, protein thiols may also be directly modified [20,36].…”

Section: Redox Modulation Of Protein Thiolsmentioning

confidence: 99%

“…Although most amino acid residues can be oxidized, the reversible oxidative modification of proteins mainly involves the reactivity of the free thiol (-SH) group of cysteine residues [1,2]. This side chain can exist in a number of different molecular states that can mediate activation or inactivation of the target protein [3]. Thus, thiol biochemistry plays an important role in cell biology since the redox status of critical cysteine thiols controls the structure and activity of many enzymes, receptors, transcription factors and transport proteins required for normal cell function.…”

Section: Introductionmentioning

confidence: 99%

Oxidoreductase regulation of Kv currents in rat ventricle

Liang

et al. 2008

Journal of Molecular and Cellular Cardiology

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Oxidative stress contributes to the arrhythmogenic substrate created by myocardial ischemiareperfusion partly through a shift in cell redox state, a key modulator of protein function. The activity of many oxidation-sensitive proteins is controlled by oxidoreductase systems that regulate the redox state of cysteine thiol groups, but the impact of these systems on ion channel function is not well defined. Thus, we examined the roles of the thioredoxin and glutaredoxin systems in controlling K + channels in the ventricle. An oxidative shift in redox state was elicited in isolated rat ventricular myocytes by brief exposure to diamide, a thiol-specific, membrane-permeable oxidant. Voltageclamp studies showed that diamide decreased peak outward K + current (I peak ) evoked by depolarizing test pulses by 41% (+60 mV; p<0.05) while steady-state outward current (I ss ) measured at the end of the test pulse was decreased by 45% (p<0.05). These electrophysiological effects were not prevented by protein kinase C blockers, but the tyrosine kinase inhibitors genistein or lavendustin A blocked the suppression of both K + currents by diamide. Moreover, inhibition of I peak and I ss by diamide was reversed by dichloroacetate and an insulin-mimetic. The effect of dichloroacetate to normalize I peak after diamide was blocked by the thioredoxin system inhibitors auranofin or 13-cisretinoic acid, but I ss was not affected by either compound. A pan-specific inhibitor of glutaredoxin and thioredoxin systems, 1,3-bis-(2-chloroethyl)-1-nitrosourea, also blocked the dichloroacetate effect on I peak but only partially inhibited the recovery of I ss . These data suggest that acute regulation of cardiac K + channels by oxidoreductase systems is mediated by redox-sensitive tyrosine kinase/ phosphatase pathways. The pathways controlling I peak channels are targets of the thioredoxin system whereas those regulating I ss channels are likely controlled by the glutaredoxin system. Thus, cardiac oxidoreductase systems may be important regulators of ion channels affected by pathogenic oxidative stress.

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“…A growing number of proteins have been identified that are not damaged by reactive oxygen species, but rather use the oxidation state of one or more reactive cysteines to modulate their activity in response to oxidative stress 5 . One such protein is the redox-regulated molecular chaperone Hsp33 from Escherichia coli.…”

mentioning

confidence: 99%

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

Ilbert

Horst

Ahrens

et al. 2007

Nat Struct Mol Biol

167

205

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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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Thiol-Based Regulatory Switches

Cited by 263 publications

References 110 publications

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

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

Oxidoreductase regulation of Kv currents in rat ventricle

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

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