title: The structural basis for the negative regulation of thioredoxin by thioredoxin-interacting protein.
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.
authors.affiliation: 1] Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea [2] Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.
authors.forename: Jungwon
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.
authors.forename: Hyun-Woo
authors.initials: HW
authors.lastname: Suh
authors.affiliation: College of Pharmacy, Korea University, Sejong 339-700, Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Jeon
authors.affiliation: Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Chungbuk 363-883, Korea.
authors.forename: Eunha
authors.initials: E
authors.lastname: Hwang
authors.affiliation: Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.
authors.forename: Loi T
authors.initials: LT
authors.lastname: Nguyen
authors.affiliation: 1] BRI, Korea Institute of Science and Technology, Seoul 136-791, Korea [2] Department of Biological Chemistry, University of Science and Technology, Daejeon 305-333, Korea.
authors.forename: Jeonghun
authors.initials: J
authors.lastname: Yeom
authors.affiliation: Biochemicals and Synthetic Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.
authors.forename: Seung-Goo
authors.initials: SG
authors.lastname: Lee
authors.affiliation: 1] BRI, Korea Institute of Science and Technology, Seoul 136-791, Korea [2] Department of Biological Chemistry, University of Science and Technology, Daejeon 305-333, Korea.
authors.forename: Cheolju
authors.initials: C
authors.lastname: Lee
authors.affiliation: School of Life Science and Biotechnology, Kyungpook National University, Daegu 702-701, Korea.
authors.forename: Kyung Jin
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: School of Life Science and Biotechnology, Kyungpook National University, Daegu 702-701, Korea.
authors.forename: Beom Sik
authors.initials: BS
authors.lastname: Kang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon 301-721, Korea.
authors.forename: Jin-Ok
authors.initials: JO
authors.lastname: Jeong
authors.affiliation: Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.
authors.forename: Tae-Kwang
authors.initials: TK
authors.lastname: Oh
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea.
authors.forename: Inpyo
authors.initials: I
authors.lastname: Choi
authors.affiliation: Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
authors.forename: Jie-Oh
authors.initials: JO
authors.lastname: Lee
authors.affiliation: 1] Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea [2] Biosystems and Bioengineering Program, University of Science and Technology, Daejeon 305-333, Korea.
authors.forename: Myung Hee
authors.initials: MH
authors.lastname: Kim
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010084:Oxidation-Reduction; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species; D013879:Thioredoxins / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D004220:Disulfides; D017382:Reactive Oxygen Species; C491203:TXN protein, human; C486715:TXNIP protein, human; D013879:Thioredoxins