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The structural basis for the negative regulation of thioredoxin by thioredoxin-interacting protein.

<div class='caption-title'>Overall structure of the heterodimeric complex of TRX and TXNIP in the asymmetric unit.</div>
<div class='caption-title'>Representative structure of the TRX and TXNIP complex and structural comparison between TXNIP and arrestin.</div>
<div class='caption-title'>Detailed characterization of the TRX–TXNIP interaction.</div>
Hwang J, Suh HW, Jeon YH, Hwang E, Nguyen LT, Yeom J, Lee SG, Lee C, Kim KJ, Kang BS, Jeong JO, Oh TK, Choi I, Lee JO, Kim MH
OpenAccess logo Nat Commun 5 2958 (2014)
Related entries: 4gfx, 4ll4

Cited: 85 times
EuropePMC logo PMID: 24389582

Abstract

The redox-dependent inhibition of thioredoxin (TRX) by thioredoxin-interacting protein (TXNIP) plays a pivotal role in various cancers and metabolic syndromes. However, the molecular mechanism of this regulation is largely unknown. Here, we present the crystal structure of the TRX-TXNIP complex and demonstrate that the inhibition of TRX by TXNIP is mediated by an intermolecular disulphide interaction resulting from a novel disulphide bond-switching mechanism. Upon binding to TRX, TXNIP undergoes a structural rearrangement that involves switching of a head-to-tail interprotomer Cys63-Cys247 disulphide between TXNIP molecules to an interdomain Cys63-Cys190 disulphide, and the formation of a de novo intermolecular TXNIP Cys247-TRX Cys32 disulphide. This disulphide-switching event unexpectedly results in a domain arrangement of TXNIP that is entirely different from those of other arrestin family proteins. We further show that the intermolecular disulphide bond between TRX and TXNIP dissociates in the presence of high concentrations of reactive oxygen species. This study provides insight into TRX and TXNIP-dependent cellular regulation.

Reviews - 4ll1 mentioned but not cited (1)

  1. The Diverse Roles of Arrestin Scaffolds in G Protein-Coupled Receptor Signaling. Peterson YK, Luttrell LM. Pharmacol Rev 69 256-297 (2017)

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  22. The role of TXNIP in cancer: a fine balance between redox, metabolic, and immunological tumor control. Deng J, Pan T, Liu Z, McCarthy C, Vicencio JM, Cao L, Alfano G, Suwaidan AA, Yin M, Beatson R, Ng T. Br J Cancer 129 1877-1892 (2023)
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  24. Reductive Reprogramming: A Not-So-Radical Hypothesis of Neurodegeneration Linking Redox Perturbations to Neuroinflammation and Excitotoxicity. Foley TD. Cell Mol Neurobiol 39 577-590 (2019)
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