Redox regulation of c-Jun DNA binding by reversible S-glutathiolation

Redox control of the transcription factor c-Jun maps to a single cysteine i n its DNA binding domain. However, the nature of the oxidized state of this cysteine and, thus, the potential molecular mechanisms accounting for the redox regulation of c-Jun DNA binding remain unclear. To address this issue , we have analyzed the purified recombinant c-Jun DNA binding domain for re dox-dependent thiol modifications and concomitant changes in DNA binding ac tivity. We show that changes in the ratio of reduced to oxidized glutathion e provide the potential to oxidize c-Jun sulfhydryls by mechanisms that inc lude both protein disulfide formation and S-glutathiolation, We provide evi dence that S-glutathiolation, which is specifically targeted to the cystein e residue located in the DNA binding site of the protein, may account for t he reversible redox regulation of c-Jun DNA binding. Furthermore, based on a molecular model of the S-glutathiolated protein, we discuss the structura l elements facilitating S-glutathiolation and how this modification interfe res with DNA binding, Given the structural similarities between the positiv ely charged cysteine-containing DNA binding motif of c-Jun and the DNA bind ing site of related oxidant-sensitive transcriptional activators, the unpre cedented phenomenon of redox-triggered S-thiolation of a transcription fact or described in this report suggests a novel role for protein thiolation in the redox control of transcription.