title: Redox regulation of the human dual specificity phosphatase YVH1 through disulfide bond formation.
abstract: YVH1 was one of the first eukaryotic dual specificity phosphatases cloned, and orthologues poses a unique C-terminal zinc-coordinating domain in addition to a cysteine-based phosphatase domain. Our recent results revealed that human YVH1 (hYVH1) protects cells from oxidative stress. This function requires phosphatase activity and the zinc binding domain. This current study provides evidence that the thiol-rich zinc-coordinating domain may act as a redox sensor to impede the active site cysteine from inactivating oxidation. Furthermore, using differential thiol labeling and mass spectrometry, it was determined that hYVH1 forms intramolecular disulfide bonds at the catalytic cleft as well as within the zinc binding domain to avoid irreversible inactivation during severe oxidative stress. Importantly, zinc ejection is readily reversible and required for hYVH1 activity upon returning to favorable conditions. This inimitable mechanism provides a means for hYVH1 to remain functionally responsive for protecting cells during oxidative stimuli.
authors: Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario N9B 3P4, Canada.
authors: Christopher A
authors: CA
authors: Bonham
authors: Panayiotis O
authors: PO
authors: Vacratsis
mesh_terms: D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D004220:Disulfides / Q000737:chemistry*; D054638:Dual Specificity Phosphatase 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D011485:Protein Binding; D011487:Protein Conformation; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015032:Zinc / Q000378:metabolism
chemical_list: D004220:Disulfides; D016877:Oxidants; D006861:Hydrogen Peroxide; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D015032:Zinc