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

Jungwon Hwang1, Hyun-Woo Suh2, Young Ho Jeon3

  • 11] Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea [2] Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.

Nature Communications
|January 7, 2014
PubMed

Insights

Thioredoxin-interacting protein (TXNIP) inhibits thioredoxin (TRX) via a novel disulfide bond-switching mechanism. This interaction, crucial in cancer and metabolic diseases, is reversed by reactive oxygen species.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Background:

  • Thioredoxin (TRX) and thioredoxin-interacting protein (TXNIP) regulate cellular redox balance.
  • TXNIP's redox-dependent inhibition of TRX is implicated in cancers and metabolic syndromes.
  • The precise molecular mechanism of TRX-TXNIP regulation remains poorly understood.

Purpose of the Study:

  • To elucidate the molecular mechanism by which TXNIP inhibits TRX.
  • To determine the crystal structure of the TRX-TXNIP complex.
  • To investigate the role of disulfide bonds in TRX-TXNIP interaction and regulation.

Main Methods:

  • X-ray crystallography to determine the TRX-TXNIP complex structure.
  • Biochemical assays to analyze disulfide bond formation and switching.
  • Investigation of the effect of reactive oxygen species on the complex.

Main Results:

  • The crystal structure reveals a novel disulfide bond-switching mechanism in TXNIP upon binding TRX.
  • TXNIP forms an intermolecular disulfide bond (Cys247-TRX Cys32) with TRX, inhibiting its activity.
  • This disulfide bond dissociates under high reactive oxygen species concentrations.

Conclusions:

  • TXNIP inhibits TRX through a unique disulfide bond-switching mechanism, altering TXNIP's domain arrangement.
  • The TRX-TXNIP interaction is redox-sensitive and reversible.
  • This provides critical insights into cellular regulation by TRX and TXNIP.

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