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

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Title
The structural basis for the negative regulation of thioredoxin by thioredoxin-interacting protein
Author(s)
Jungwon Hwang; H W Suh; Y H Jeon; E Hwang; L T Nguyen; J Yeom; Seung Goo Lee; C Lee; K J Kim; B S Kang; J O Jeong; Tae Kwang Oh; In Pyo Choi; J O Lee; Myung Hee Kim
Bibliographic Citation
Nature Communications, vol. 5, pp. 2958-2958
Publication Year
2014
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.
ISSN
2041-1723
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/ncomms3958
Type
Article
Appears in Collections:
Division of Biomedical Research > Microbiome Convergence Research Center > 1. Journal Articles
Synthetic Biology and Bioengineering Research Institute > 1. Journal Articles
Division of Biomedical Research > Metabolic Regulation Research Center > 1. Journal Articles
Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
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