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

Author

Listed:
  • Jungwon Hwang

    (Korea Advanced Institute of Science and Technology
    Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology)

  • Hyun-Woo Suh

    (Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology)

  • Young Ho Jeon

    (College of Pharmacy, Korea University)

  • Eunha Hwang

    (Korea Basic Science Institute, Ochang)

  • Loi T. Nguyen

    (Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology)

  • Jeonghun Yeom

    (BRI, Korea Institute of Science and Technology
    University of Science and Technology)

  • Seung-Goo Lee

    (Biochemicals and Synthetic Biology Research Center, Korea Research Institute of Bioscience and Biotechnology)

  • Cheolju Lee

    (BRI, Korea Institute of Science and Technology
    University of Science and Technology)

  • Kyung Jin Kim

    (School of Life Science and Biotechnology, Kyungpook National University)

  • Beom Sik Kang

    (School of Life Science and Biotechnology, Kyungpook National University)

  • Jin-Ok Jeong

    (Chungnam National University School of Medicine)

  • Tae-Kwang Oh

    (Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology)

  • Inpyo Choi

    (Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology)

  • Jie-Oh Lee

    (Korea Advanced Institute of Science and Technology)

  • Myung Hee Kim

    (Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology
    Biosystems and Bioengineering Program, University of Science and Technology)

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.

Suggested Citation

  • Jungwon Hwang & Hyun-Woo Suh & Young Ho Jeon & Eunha Hwang & Loi T. Nguyen & Jeonghun Yeom & Seung-Goo Lee & Cheolju Lee & Kyung Jin Kim & Beom Sik Kang & Jin-Ok Jeong & Tae-Kwang Oh & Inpyo Choi & Ji, 2014. "The structural basis for the negative regulation of thioredoxin by thioredoxin-interacting protein," Nature Communications, Nature, vol. 5(1), pages 1-14, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms3958
    DOI: 10.1038/ncomms3958
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