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.
Jie Jia  1 ,  Abul Arif  1 ,  Fulvia Terenzi  1 ,  Belinda Willard  2 ,  Edward F Plow  3 ,  Stanley L Hazen  1 ,  Paul L Fox  4
Affiliations
  • 1. Department of Cellular and Molecular Medicine, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 2. Mass Spectrometry Laboratory for Protein Sequencing, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 3. Department of Molecular Cardiology, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 4. Department of Cellular and Molecular Medicine, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: [email protected].
PMID: 25417112 DOI: 10.1016/j.cell.2014.09.032
Abstract

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.