Regulation of the Catalytic Activity and Structure of Human Thioredoxin 1 via Oxidation and S-Nitrosylation of Cysteine Residues

Hashemy, Seyed Isaac; Holmgren, Arne

doi:10.1074/jbc.m801047200

Cited by 171 publications

(160 citation statements)

References 59 publications

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“…Considering that Trx1 is susceptible to inhibitory oxidation by high concentrations of oxidants, as found here and also shown earlier (33,40), it is notable that TRP14 was resistant to such inhibition. The intracellular removal of H 2 O 2 in cells is mediated mainly by the cytosolic peroxiredoxins using reducing equivalents provided by Trx, so a direct peroxidase activity of Trx is not likely (41).…”

Section: Discussionmentioning

confidence: 61%

Thioredoxin-related protein of 14 kDa is an efficient L-cystine reductase and S-denitrosylase

Pader

Sengupta

Cebula

et al. 2014

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

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134

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Thioredoxin-related protein of 14 kDa (TRP14, also called TXNDC17 for thioredoxin domain containing 17, or TXNL5 for thioredoxinlike 5) is an evolutionarily well-conserved member of the thioredoxin (Trx)-fold protein family that lacks activity with classical Trx1 substrates. However, we discovered here that human TRP14 has a high enzymatic activity in reduction of L-cystine, where the catalytic efficiency (2,217 min) coupled to Trx reductase 1 (TrxR1) using NADPH was fivefold higher compared with Trx1 (418 min). Moreover, the L-cystine reduction with TRP14 was in contrast to that of Trx1 fully maintained in the presence of a protein disulfide substrate of Trx1 such as insulin, suggesting that TRP14 is a more dedicated L-cystine reductase compared with Trx1. We also found that TRP14 is an efficient S-denitrosylase with similar efficiency as Trx1 in catalyzing TrxR1-dependent denitrosylation of S-nitrosylated glutathione or of HEK293 cell-derived S-nitrosoproteins. Consequently, nitrosylated and thereby inactivated caspase 3 or cathepsin B could be reactivated through either Trx1-or TRP14-catalyzed denitrosylation reactions. TRP14 was also, in contrast to Trx1, completely resistant to inactivation by high concentrations of hydrogen peroxide. The oxidoreductase activities of TRP14 thereby complement those of Trx1 and must therefore be considered for the full understanding of enzymatic control of cellular thiols and nitrosothiols.redox regulation | nitric oxide | sulfur metabolism | oxidative stress

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Section: Discussionmentioning

confidence: 61%

Thioredoxin-related protein of 14 kDa is an efficient L-cystine reductase and S-denitrosylase

Pader

Sengupta

Cebula

et al. 2014

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

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134

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“…Each of these has been implicated in S-nitrosation activities (also called S-nitrosylation), particularly with respect to regulation of apoptosis. [7][8][9][10][11][12][13][14] S-nitrosation/nitrosylation is the addition of NO to a cysteine residue, a redox reaction requiring one electron oxidation, and numerous proteins have been suggested to be regulated in this manner. 15 Removal of the nitroso group in target proteins, or transfer of the group to other proteins, is likely to involve hTrx1 in human cells.…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of human thioredoxin revealing an unraveled helix and exposed S‐nitrosation site

Weichsel¹,

Kem²,

Montfort³

2010

Protein Science

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Thioredoxins reduce disulfide bonds and other thiol modifications in all cells using a CXXC motif. Human thioredoxin 1 is unusual in that it codes for an additional three cysteines in its 105 amino acid sequence, each of which have been implicated in other reductive activities. Cys 62 and Cys 69 are buried in the protein interior and lie at either end of a short helix (helix 3), and yet can disulfide link under oxidizing conditions. Cys 62 is readily S-nitrosated, giving rise to a SNO modification, which is also buried. Here, we present two crystal structures of the C69S/C73S mutant protein under oxidizing (1.5 Å ) and reducing (1.1 Å ) conditions. In the oxidized structure, helix 3 is unraveled and displays a new conformation that is stabilized by a series of new hydrogen bonds and a disulfide link with Cys 62 in a neighboring molecule. The new conformation provides an explanation for how a completely buried residue can participate in SNO exchange reactions.

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“…Trx1 is localized in the cell cytosol/nucleus, whereas Trx2 is a mitochondrial protein (4). In addition to the active site Cys-32 and Cys-35, mammalian Trx1 has three non-active site cysteine residues (Cys-62, Cys-69, and Cys-73), which have been suggested to be important for regulating the activity and function of Trx1 (12). Cys-62 and Cys-69 are within helix ␣3, and Cys-73 is on a hydrophobic patch of surface of the protein.…”

mentioning

confidence: 99%

Thioredoxin 1 Is Inactivated Due to Oxidation Induced by Peroxiredoxin under Oxidative Stress and Reactivated by the Glutaredoxin System

Du¹,

Zhang²,

Zhang

et al. 2013

Journal of Biological Chemistry

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Background:The Cys-62/Cys-69 dithiol of Trx1 is predicted to have a profound effect on cell signaling. Results: The Cys-62/Cys-69 dithiol of Trx1 was oxidized by Prx1, and this disulfide was reduced by the GSH/glutaredoxin system. Conclusion: Trx1 is involved in redox regulation via reversible oxidation of the Cys-62/Cys-69 dithiol of Trx1. Significance: We demonstrated the critical role of Trx1 oxidation in cell signaling.

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Regulation of the Catalytic Activity and Structure of Human Thioredoxin 1 via Oxidation and S-Nitrosylation of Cysteine Residues

Abstract: The mammalian cytosolic/nuclear thioredoxin system, comprising thioredoxin (Trx), selenoenzyme thioredoxin reductase (TrxR), and NADPH, is the major protein-disulfide reductase of the cell and has numerous functions.

Cited by 171 publications

References 59 publications

Thioredoxin-related protein of 14 kDa is an efficient L-cystine reductase and S-denitrosylase

Thioredoxin-related protein of 14 kDa is an efficient L-cystine reductase and S-denitrosylase

Crystal structure of human thioredoxin revealing an unraveled helix and exposed S‐nitrosation site

Thioredoxin 1 Is Inactivated Due to Oxidation Induced by Peroxiredoxin under Oxidative Stress and Reactivated by the Glutaredoxin System

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