title: The interaction of thioredoxin with Txnip. Evidence for formation of a mixed disulfide by disulfide exchange.
abstract: 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.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts 02139. Electronic address: ppatwari@rics.bwh.harvard.edu.
authors.forename: Parth
authors.initials: P
authors.lastname: Patwari
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts 02139.
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Higgins
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts 02139.
authors.forename: William A
authors.initials: WA
authors.lastname: Chutkow
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts 02139.
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshioka
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, Massachusetts 02139.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D017124:Conserved Sequence; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010084:Oxidation-Reduction; D011485:Protein Binding; D013879:Thioredoxins / Q000378:metabolism*; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D004220:Disulfides; C486715:TXNIP protein, human; D013879:Thioredoxins; D003545:Cysteine