Target-selective protein S-nitrosylation by sequence motif recognition

Cell. 2014 Oct 23;159(3):623-34. doi: 10.1016/j.cell.2014.09.032. Epub 2014 Oct 16.


S-nitrosylation is a ubiquitous protein modification emerging as a principal mechanism of nitric oxide (NO)-mediated signal transduction and cell function. S-nitrosylases can use NO synthase (NOS)-derived NO to modify selected cysteines in target proteins. Despite proteomic identification of over a thousand S-nitrosylated proteins, few S-nitrosylases have been identified. Moreover, mechanisms underlying site-selective S-nitrosylation and the potential role of specific sequence motifs remain largely unknown. Here, we describe a stimulus-inducible, heterotrimeric S-nitrosylase complex consisting of inducible NOS (iNOS), S100A8, and S100A9. S100A9 exhibits transnitrosylase activity, shuttling NO from iNOS to the target protein, whereas S100A8 and S100A9 coordinately direct site selection. A family of proteins S-nitrosylated by iNOS-S100A8/A9 were revealed by proteomic analysis. A conserved I/L-X-C-X2-D/E motif was necessary and sufficient for iNOS-S100A8/A9-mediated S-nitrosylation. These results reveal an elusive parallel between protein S-nitrosylation and phosphorylation, namely, stimulus-dependent posttranslational modification of selected targets by primary sequence motif recognition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Calgranulin A / metabolism
  • Calgranulin B / metabolism
  • Glyceraldehyde-3-Phosphate Dehydrogenases / chemistry
  • Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism
  • Humans
  • Interferon-gamma / metabolism
  • Lipoproteins, LDL / metabolism
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Multiprotein Complexes / metabolism*
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / metabolism*
  • Protein Processing, Post-Translational*
  • Proteins / chemistry*
  • Proteins / metabolism*
  • Sequence Alignment


  • Calgranulin A
  • Calgranulin B
  • Lipoproteins, LDL
  • Multiprotein Complexes
  • Proteins
  • Nitric Oxide
  • Interferon-gamma
  • Nitric Oxide Synthase Type II
  • Glyceraldehyde-3-Phosphate Dehydrogenases