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J. Biol. Chem., Vol. 278, Issue 46, 45325-45332, November 14, 2003

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Thioredoxin 2, an Oxidative Stress-induced Protein, Contains a High Affinity Zinc Binding Site^*

Jean-Francois Collet¶, Jonathan Conrad D'Souza, Ursula Jakob||, and James C. A. Bardwell**

From the Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109-1048 and the Laboratoire de Chimie Physiologique, Université Catholique de Louvain, B-1200 Brussels, Belgium

Two thioredoxins have been described in Escherichia coli, TrxA and Trx2. Both thioredoxins are capable of reducing disulfide bonds using a conserved pair of cysteine residues present in a WCGPC motif. A number of unique structural and regulatory features distinguish the Trx2 subfamily from the much larger TrxA family. The Trx2 subfamily has an additional N-terminal domain of ± 30 residues, which contains two additional conserved CXXC motifs. Moreover, the gene coding for Trx2 is under control of the oxidative stress transcription factor OxyR in E. coli. This suggests that Trx2 may play a role in the cellular defense against oxidative stress. We show here that Trx2 contains zinc in a 1:1 stoichiometry, making it the first identified zinc-binding thioredoxin. The zinc atom is coordinated by the four cysteines of the two N-terminal CXXC motifs. The zinc center of Trx2 binds zinc with a very high affinity (K_a of >10¹⁸ M^–1). We show that in vitro oxidation of the zinc binding cysteines by H₂O₂ releases the zinc and induces a conformational change. The zinc-free protein conserves its reductase activity. Altogether, our results suggest that the zinc center might play the role of a redox switch, changing a yet to be identified activity.

Received for publication, July 18, 2003 , and in revised form, August 28, 2003.

^* This work was supported by National Institutes of Health Grants GM064662 (to J. C. A. B.) and GM065318 (to U. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Charge de Recherches of the Belgian Fonds National de la Recherche Scientifique.

^|| A Burroughs Wellcome Fund Scholar.

^** To whom correspondence should be addressed. Tel.: 1-734-764-8028; Fax: 1-734-647-0884; E-mail: jbardwel{at}umich.edu.

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