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

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, Jie-Oh Lee and Myung Hee Kim ()
Additional contact information
Jungwon Hwang: Korea Advanced Institute of Science and Technology
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
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
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

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms3958

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