Cysteine perthiosulfenic acid (Cys-SSOH): A novel intermediate in thiol-based redox signaling?
David E. Heppner,
Milena Hristova,
Tomoaki Ida,
Ana Mijuskovic,
Christopher M. Dustin,
Virág Bogdándi,
Jon M. Fukuto,
Tobias P. Dick,
Péter Nagy,
Jianing Li,
Takaaki Akaike,
Albert van der Vliet
Affiliations
David E. Heppner
Department of Pathology and Laboratory Medicine, Robert Larner M.D., College of Medicine, University of Vermont, Burlington, VT, USA
Milena Hristova
Department of Pathology and Laboratory Medicine, Robert Larner M.D., College of Medicine, University of Vermont, Burlington, VT, USA
Tomoaki Ida
Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan
Ana Mijuskovic
Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany
Christopher M. Dustin
Department of Pathology and Laboratory Medicine, Robert Larner M.D., College of Medicine, University of Vermont, Burlington, VT, USA
Virág Bogdándi
Department of Molecular Immunology and Toxicology, National Institute of Oncology, Budapest, Hungary
Jon M. Fukuto
Department of Chemistry, Sonoma State University, Rohnert Park, CA, USA
Tobias P. Dick
Division of Redox Regulation, DKFZ-ZMBH Alliance, German Cancer Research Center (DKFZ), Heidelberg, Germany
Péter Nagy
Department of Molecular Immunology and Toxicology, National Institute of Oncology, Budapest, Hungary
Jianing Li
Department of Chemistry, University of Vermont, Burlington, VT, USA
Takaaki Akaike
Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, Japan; Corresponding authors.
Albert van der Vliet
Department of Pathology and Laboratory Medicine, Robert Larner M.D., College of Medicine, University of Vermont, Burlington, VT, USA; Corresponding authors.
The reversible oxidation of protein cysteine residues (Cys-SH) is a key reaction in cellular redox signaling involving initial formation of sulfenic acids (Cys-SOH), which are commonly detected using selective dimedone-based probes. Here, we report that significant portions of dimedone-tagged proteins are susceptible to cleavage by DTT reflecting the presence of perthiosulfenic acid species (Cys-SSOH) due to similar oxidation of hydropersulfides (Cys-SSH), since Cys-S-dimedone adducts are stable toward DTT. Combined studies using molecular modeling, mass spectrometry, and cell-based experiments indicate that Cys-SSH are readily oxidized to Cys-SSOH, which forms stable adducts with dimedone-based probes. We additionally confirm the presence of Cys-SSH within protein tyrosine kinases such as EGFR, and their apparent oxidation to Cys-SSOH in response NADPH oxidase activation, suggesting that such Cys-SSH oxidation may represent a novel, as yet uncharacterized, event in redox-based signaling. Keywords: Thiol oxidation, Sulfenic acid, Dimedone, Hydrogen peroxide, NADPH oxidase, Redox signaling
