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J. Biol. Chem., Vol. 281, Issue 31, 21884-21891, August 4, 2006

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The Interaction of Thioredoxin with Txnip

EVIDENCE FOR FORMATION OF A MIXED DISULFIDE BY DISULFIDE EXCHANGE^*

From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts 02139

The thioredoxin system plays an important role in maintaining a reducing environment in the cell. Recently, several thioredoxin binding partners have been identified and proposed to mediate aspects of redox signaling, but the significance of these interactions is unclear in part due to incomplete understanding of the mechanism for thioredoxin binding. Thioredoxin-interacting protein (Txnip) is critical for regulation of glucose metabolism, the only currently known function of which is to bind and inhibit thioredoxin. We explored the mechanism of the Txnip-thioredoxin interaction and present evidence that Txnip and thioredoxin form a stable disulfide-linked complex. We identified two Txnip cysteines that are important for thioredoxin binding and showed that this interaction is consistent with a disulfide exchange reaction between oxidized Txnip and reduced thioredoxin. These cysteines are not conserved in the broader family of arrestin domain-containing proteins, and we demonstrate that the thioredoxin-binding property of Txnip is unique. These data suggest that Txnip is a target of reduced thioredoxin and provide insight into the potential role of Txnip as a redox-sensitive signaling protein.

Received for publication, January 17, 2006 , and in revised form, April 27, 2006.

^* This work was supported by grants from the National Institutes of Health (NIH) (to R. T. L.) and an NIH National Research Service Award (to P. P.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Brigham and Women's Hospital, Partners Research Bldg., Rm. 280, 65 Landsdowne St., Cambridge, MA 02139. Tel.: 617-768-8283; Fax: 617-768-8280; E-mail: ppatwari{at}rics.bwh.harvard.edu.

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