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

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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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2014-01
Language
English
Article Type
Article
Keywords

BINDING PROTEIN-2; OXIDATIVE STRESS; DEPENDENT DEGRADATION; MIXED DISULFIDE; TXNIP; EXPRESSION; CANCER; GLUCOSE; ARRESTIN; TARGET

Citation

NATURE COMMUNICATIONS, v.5, pp.2958 - 2958

ISSN
2041-1723
DOI
10.1038/ncomms3958
URI
http://hdl.handle.net/10203/189714
Appears in Collection
CH-Journal Papers(저널논문)
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