title: Site-Specific Proteomic Mapping Identifies Selectively Modified Regulatory Cysteine Residues in Functionally Distinct Protein Networks.
abstract: S-Acylation, S-glutathionylation, S-nitrosylation, and S-sulfenylation are prominent, chemically distinct modifications that regulate protein function, redox sensing, and trafficking. Although the biological significance of these modifications is increasingly appreciated, their integration in the proteome remains unknown. Novel mass spectrometry-based technologies identified 2,596 predominately unique sites in 1,319 mouse liver proteins under physiological conditions. Structural analysis localized the modifications in unique, evolutionary conserved protein segments, outside commonly annotated functional regions. Contrary to expectations, propensity for modification did not correlate with biophysical properties that regulate cysteine reactivity. However, the in vivo chemical reactivity is fine-tuned for specificity, demonstrated by the nominal complementation between the four modifications and quantitative proteomics which showed that a reduction in S-nitrosylation is not correlated with increased S-glutathionylation. A comprehensive survey uncovered clustering of modifications within biologically related protein networks. The data provide the first evidence for the occurrence of distinct, endogenous protein networks that undergo redox signaling through specific cysteine modifications.
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Gould
authors.affiliation: Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Perry
authors.initials: P
authors.lastname: Evans
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Martínez-Acedo
authors.affiliation: Department of Agricultural Biotechnology, Akdeniz University, Antalya 07985, Turkey.
authors.forename: Stefano M
authors.initials: SM
authors.lastname: Marino
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Gladyshev
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Kate S
authors.initials: KS
authors.lastname: Carroll
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: ischirop@mail.med.upenn.edu.
authors.forename: Harry
authors.initials: H
authors.lastname: Ischiropoulos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003545:Cysteine / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010449:Peptide Mapping; D060066:Protein Interaction Maps; D011499:Protein Processing, Post-Translational; D020543:Proteome / Q000737:chemistry* / Q000378:metabolism*; D040901:Proteomics / Q000379:methods
chemical_list: D020543:Proteome; D003545:Cysteine