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

Jungwon Hwang, Hyun Woo Suh, Young H.o. Jeon, Eunha Hwang, Loi T. Nguyen, Jeonghun Yeom, Seung Goo Lee, Cheolju Lee, Kyung J.in Kim, Beom S.ik Kang, Jin Ok Jeong, Tae Kwang Oh, Inpyo Choi, Jie Oh Lee, Myung H.ee Kim

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

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.

Original languageEnglish
Article number2958
Pages (from-to)2958
Number of pages1
JournalNature Communications
Volume5
DOIs
StatePublished - 2014

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