Interaction between bisphenol derivatives and protein disulphide isomerase (PDI) and inhibition of PDI functions: requirement of chemical structure for binding to PDI.
Bisphenol A (BPA) is an endocrine disrupting chemical and several biological effects have been reported. Previously, protein disulphide isomerase (PDI) was isolated as a target molecule of bisphenol A. In this study, to clarify the effects of BPA on PDI functions, we investigated the relationship between the chemical structure of BPA derivatives and the effects on PDI-mediated isomerase and chaperone activity. We also investigated the effects of changes in the isomerase domain of PDI on the binding of chemicals, using PDI mutants and oxidized or reduced PDI. Among six chemicals, only chemicals, which have a phenol group, can bind to PDI and these chemicals also have an inhibitory effect on PDI-mediated isomerase activity. Changes in the structure of the PDI isomerase domain did not affect chemical-binding activity. On the other hand, the chemicals used in this study have low effects on chaperone activity of PDI. Substitutions in Cys residues (Cys398 and Cys401) of the isomerase active site changed chaperone activity. The present study indicates that phenolic compounds specifically bind to PDI and inhibit isomerase activity. This study provides useful information to predict the biological effects of chemicals and structural studies of PDI containing the function of chemical binding.
Department of Bioscience, Nanobiotechnology Research Center, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337, Japan.
Shoko
S
Hashimoto
Kazushi
K
Okada
Susumu
S
Imaoka
D000818:Animals; D001559:Benzhydryl Compounds; D001665:Binding Sites; D001667:Binding, Competitive; D003545:Cysteine / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D008954:Models, Biological; D008956:Models, Chemical; D018832:Molecular Chaperones / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry; D010636:Phenols / Q000737:chemistry; D011485:Protein Binding; D019704:Protein Disulfide-Isomerases / Q000737:chemistry*; D017510:Protein Folding; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D003545:Cysteine; D006639:Histidine; D018832:Molecular Chaperones; D010100:Oxygen; D010636:Phenols; D019704:Protein Disulfide-Isomerases; D011993:Recombinant Fusion Proteins; C006780:bisphenol A; D000098826:Bisphenol A Compounds