[HTML][HTML] Nitrosylation: the prototypic redox-based signaling mechanism

JS Stamler, S Lamas, FC Fang - Cell, 2001 - cell.com
Cell, 2001cell.com
Two signaling systems, based on the principle of posttranslational modification of proteins,
are conserved throughout evolution and influence most aspects of cellular physiology—one
is phosphorylation and the other is redox based. Both exemplify dynamic regulation of
protein function by reversible modification, and they govern many of the same signal
transduction pathways through overlapping sets of cellular targets. They are also prone to
malfunction in human disease. However, while many basic principles of signal transduction …
Two signaling systems, based on the principle of posttranslational modification of proteins, are conserved throughout evolution and influence most aspects of cellular physiology—one is phosphorylation and the other is redox based. Both exemplify dynamic regulation of protein function by reversible modification, and they govern many of the same signal transduction pathways through overlapping sets of cellular targets. They are also prone to malfunction in human disease. However, while many basic principles of signal transduction have emerged from studies of phosphorylation, the redox-based mechanism has remained far more enigmatic. A major difficulty has been to comprehend how specificity of action is achieved. Recent advances in understanding how nitric oxide (NO) regulates protein function are now providing answers. At the recent Juan March Foundation Workshop on “Regulation of Protein Function by Nitric Oxide (Nitrosylation and Nitrosative Stress),” several core principles emerged. First, NO groups modify cysteine thiols and transition metal centers of a broad functional spectrum of proteins, and with remarkable spatial and temporal resolution (for over 100 representative examples, see Table S1 in Supplementary Material available online at http://www. cell. com/cgi/content/full/106/6/675/DC1). Second, the majority of these proteins are regulated by S-nitrosylation of a single critical cysteine residue within an acid-base or hydrophobic structural motif, which may also be subject to oxygen-or glutathione-dependent modification. Thus, S-nitrosylation emerges as a prototypic redox-based signal. Third, the same NO-related posttranslational modifications that operate as specific signals in mammalian cells can be used to fight invasion by microbes and cancer cells. That is, nitrosylation can disrupt the function of critical proteins in pathologically proliferating cells in what is referred to as nitrosative stress. This theme will be dealt with in greater detail in the latter part of this report, which focuses on antimicrobial actions of NO and the cellular defense mechanisms that protect specifically against NO-related species, as well as on the deleterious consequences of redox-based modification of proteins.
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