Figure 8: Proposed molecular mechanism of the negative regulation of TRX by TXNIP.
From: The structural basis for the negative regulation of thioredoxin by thioredoxin-interacting protein
The inhibition of TRX by TXNIP is regulated by a redox-dependent disulphide bond-switching mechanism. Under normoxic conditions, TXNIP binds to TRX through an intermolecular disulphide bond formed between TXNIP Cys247 and TRX Cys32 and inhibits its reducing activity. During oxidative stress, high levels of ROS may cause further oxidation of this bond and lead to the dissociation of TXNIP from TRX. ROS also likely trigger antioxidant pathways to restore a reducing environment. After restoration of a reductive redox potential, the active cysteines of TRX may interact with the interprotomer disulphide bond between Cys63 and Cys247 of TXNIP molecules. Subsequently, TXNIP molecules would undergo a structural rearrangement that involves switching of the interprotomer disulphide bond between TXNIP molecules to an interdomain Cys63-Cys190 disulphide bond, and the formation of a de novo intermolecular TXNIP Cys247-TRX Cys32 disulphide bond. See discussion for a full description. TRX and TXNIP are shown in yellow and cyan, respectively. Cysteine residues forming disulphide bonds are displayed in brown.
