title: Red/ox states of human protein disulfide isomerase regulate binding affinity of 17 beta-estradiol.
abstract: Human protein disulfide isomerase (hPDI) is a key redox-regulated thiol-containing protein operating as both oxidoreductase and molecular chaperone in the endoplasmic reticulum of cells. hPDI thiol-disulfide interchange reactions lead to the adoption of two distinct red/ox conformations with different substrate preferences. hPDI also displays high binding capacity for some endogenous steroid hormones including 17 beta-estradiol (E2) and thus contributes to the regulation of their intracellular concentration, storage and actions. The primary focus of this study was to investigate the impact of E2 binding on functional activity of recombinant hPDI. Then, we examined the effect of E2 binding on structural alteration of hPDI red/ox conformations and its influence on affinity and position of interaction using experimental and computational analysis. Our results revealed that interaction of one E2 per each hPDI molecule led to the inhibition of hPDI reductase activity and conformational changes in both oxidation states. Mutually, E2-binding position were also redox-regulated with higher affinity in oxidized hPDI compare to the reduced form. The importance of histidine-256 protonation states in distinct binding preferences of E2 were also demonstrated in hPDI red/ox conformations. These findings might pave the way for better understanding of the mechanisms behind the redox-dependent hormone-binding activity of hPDI.
authors.affiliation: Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
authors.forename: Razieh
authors.initials: R
authors.lastname: Karamzadeh
authors.affiliation: Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
authors.forename: Mohammad Hossein
authors.initials: MH
authors.lastname: Karimi-Jafari
authors.affiliation: Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
authors.forename: Ali Akbar
authors.initials: AA
authors.lastname: Saboury
authors.affiliation: Department of Molecular Systems Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. Electronic address: salekdeh@royaninstitute.org.
authors.forename: Ghasem Hosseini
authors.initials: GH
authors.lastname: Salekdeh
authors.affiliation: Department of Biophysics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. Electronic address: moosavi@ut.ac.ir.
authors.forename: Ali Akbar
authors.initials: AA
authors.lastname: Moosavi-Movahedi
mesh_terms: D003001:Cloning, Molecular; D004220:Disulfides / Q000737:chemistry; D004958:Estradiol / Q000737:chemistry*; D004967:Estrogens / Q000737:chemistry; D006639:Histidine / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D019704:Protein Disulfide-Isomerases / Q000737:chemistry*; D012984:Software; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D004220:Disulfides; D004967:Estrogens; D013438:Sulfhydryl Compounds; D006639:Histidine; D004958:Estradiol; D019704:Protein Disulfide-Isomerases; D010100:Oxygen
keywords: 17 beta-estradiol (E2); 17β-Estradiol (PubChem CID: 5757); Disulfide exchange; Dithiothreitol (PubChem CID: 446094); Estrogen; Glutathione (PubChem CID: 124886); Glutathione disulfide (PubChem CID: 65359); Oxidative stress