Enzymatic control of cysteinyl thiol switches in proteins

Deponte, Marcel; Lillig, Christopher Horst

doi:10.1515/hsz-2014-0280

Cited by 62 publications

(67 citation statements)

References 100 publications

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“…This notion has been supported by (i) cysteine conservation across organisms, (ii) high cysteine reactivity under biological conditions, (iii) and frequent location of cysteines adjacent to functional sites [32–34]. Oxidation and reduction of cysteines creates a mechanism by which protein activity can be controlled through activities of cysteine-recognizing redox enzymes.…”

Section: Discussionmentioning

confidence: 99%

A novel mouse model for the identification of thioredoxin-1 protein interactions

Booze

Hansen

Vitiello

2016

Free Radical Biology and Medicine

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Thiol switches are important regulators of cellular signaling and are coordinated by several redox enzyme systems including thioredoxins, peroxiredoxins, and glutathione. Thioredoxin-1 (Trx1), in particular, is an important signaling molecule not only in response to redox perturbations, but also in cellular growth, regulation of gene expression, and apoptosis. The active site of this enzyme is a highly conserved C-G-P-C motif and the redox mechanism of Trx1 is rapid which presents a challenge in determining specific substrates. Numerous in vitro approaches have identified Trx1-dependent thiol switches; however, these findings may not be physiologically relevant and little is known about Trx1 interactions in vivo. In order to identify Trx1 targets in vivo, we generated a transgenic mouse with inducible expression of a mutant Trx1 transgene to stabilize intermolecular disulfides with protein substrates. Expression of the Trx1 “substrate trap” transgene did not interfere with endogenous thioredoxin or glutathione systems in brain, heart, lung, liver, and kidney. Following immunoprecipitation and proteomic analysis, we identified 41 homeostatic Trx1 interactions in perinatal lung, including previously described Trx1 substrates such as members of the peroxiredoxin family and collapsin response mediator protein 2. Using perinatal hyperoxia as a model of oxidative injury, we found 17 oxygen-induced interactions which included several cytoskeletal proteins which may be important to alveolar development. The data herein validates this novel mouse model for identification of tissue- and cell-specific Trx1-dependent pathways that regulate physiological signals in response to redox perturbations.

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Section: Discussionmentioning

confidence: 99%

A novel mouse model for the identification of thioredoxin-1 protein interactions

Booze

Hansen

Vitiello

2016

Free Radical Biology and Medicine

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“…Hydrogen peroxide can initiate redox-dependent signaling changes through reversible oxidation of reactive protein thiols [64]. Although cysteine oxidation by hydrogen peroxide is thermodynamically favorable, direct oxidation of protein thiols is unlikely to occur as the kinetic rate is very slow ( k ~1–10 M -1 s -1 ) with the exemption of catalytic thiols of dedicated redox enzymes including catalase, peroxiredoxins, glutathione peroxidases, and ascorbate peroxidases [17, 41, 65]. Prx3 reacts with approximately 90% of mitochondrial peroxides due to abundance and kinetic activity [17].…”

Section: Discussionmentioning

confidence: 99%

Detoxification of Mitochondrial Oxidants and Apoptotic Signaling Are Facilitated by Thioredoxin-2 and Peroxiredoxin-3 during Hyperoxic Injury

et al. 2017

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Mitochondria play a fundamental role in the regulation of cell death during accumulation of oxidants. High concentrations of atmospheric oxygen (hyperoxia), used clinically to treat tissue hypoxia in premature newborns, is known to elicit oxidative stress and mitochondrial injury to pulmonary epithelial cells. A consequence of oxidative stress in mitochondria is the accumulation of peroxides which are detoxified by the dedicated mitochondrial thioredoxin system. This system is comprised of the oxidoreductase activities of peroxiredoxin-3 (Prx3), thioredoxin-2 (Trx2), and thioredoxin reductase-2 (TrxR2). The goal of this study was to understand the role of the mitochondrial thioredoxin system and mitochondrial injuries during hyperoxic exposure. Flow analysis of the redox-sensitive, mitochondrial-specific fluorophore, MitoSOX, indicated increased levels of mitochondrial oxidant formation in human adenocarcinoma cells cultured in 95% oxygen. Increased expression of Trx2 and TrxR2 in response to hyperoxia were not attributable to changes in mitochondrial mass, suggesting that hyperoxic upregulation of mitochondrial thioredoxins prevents accumulation of oxidized Prx3. Mitochondrial oxidoreductase activities were modulated through pharmacological inhibition of TrxR2 with auranofin and genetically through shRNA knockdown of Trx2 and Prx3. Diminished Trx2 and Prx3 expression was associated with accumulation of mitochondrial superoxide; however, only shRNA knockdown of Trx2 increased susceptibility to hyperoxic cell death and increased phosphorylation of apoptosis signal-regulating kinase-1 (ASK1). In conclusion, the mitochondrial thioredoxin system regulates hyperoxic-mediated death of pulmonary epithelial cells through detoxification of oxidants and regulation of redox-dependent apoptotic signaling.

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“…Other parameters considered to predict the likelihood of a cysteine residue to act as a redox switch (see Deponte and Lillig, 2015) are much harder to predict on a global scale (Sun et al, 2012). (C) Amino acids in the human proteome have a median accessible surface area of 22.99%.…”

Section: Other Parameters That May Predict Thiol Switchesmentioning

confidence: 99%

Incidence and physiological relevance of protein thiol switches

Leichert

Dick

2015

Biological Chemistry

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A few small-molecule oxidants, most notably hydrogen peroxide, can act as messengers in signal transduction. They trigger so-called 'thiol switches', cysteine residues that are reversibly oxidized to transiently change the functional properties of their host proteins. The proteome-wide identification of functionally relevant 'thiol switches' is of significant interest. Unfortunately, prediction of redox-active cysteine residues on the basis of surface accessibility and other computational parameters appears to be of limited use. Proteomic thiol labeling approaches remain the most reliable strategy to discover new thiol switches in a hypothesis-free manner. We discuss if and how genomic knock-in strategies can help establish the physiological relevance of a 'thiol switch' on the organismal level. We conclude that surprisingly few attempts have been made to thoroughly verify the physiological relevance of thiol-based redox switches in mammalian model organisms.

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Enzymatic control of cysteinyl thiol switches in proteins

Cited by 62 publications

References 100 publications

A novel mouse model for the identification of thioredoxin-1 protein interactions

A novel mouse model for the identification of thioredoxin-1 protein interactions

Detoxification of Mitochondrial Oxidants and Apoptotic Signaling Are Facilitated by Thioredoxin-2 and Peroxiredoxin-3 during Hyperoxic Injury

Incidence and physiological relevance of protein thiol switches

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