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Nitrosylation: the next phosphorylation?

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Chemical species mediating protein nitrosylation

In contrast to phosphorylation, nitrosylation is an enzyme-independent process. The chemistry underlying nitrosylation reactions is incompletely understood and depends on whether a transition metal or cysteine is the nitrosylation target. NO itself nitrosylates transition metals whereas it is primarily NO-derived species including NO2, N2O3, and transition metal–NO adducts that nitrosylate cysteine residues [10]. NO2 is formed from a reaction of 2 moles of NO and 1 mole of O2 and is in a

Specificity of nitrosylation

Despite the fact that virtually every protein contains cysteine residues, many proteins contain transition metals, and most if not all cells produce NO, only a precisely defined subset of protein targets are nitrosylated intracellularly. This specificity is exemplified by the skeletal muscle calcium release channel/ryanodine receptor in which only 1 of 50 free thiols is S-nitrosylated [13], [14]. S-nitrosylation of this single cysteine regulates calmodulin-dependent modulation of ryanodine

Denitrosylation

Just as dephosphorylation reactions reverse the effects of phosphorylation, denitrosylation reverses nitrosylation effects. Thus phosphorylation/dephosphorylation and nitrosylation/denitrosylation may serve as on/off switches for protein function. However, unlike dephosphorylation, denitrosylation can be accomplished nonenzymatically due to the lability of S–NO and metal–NO bonds. As mentioned above, cellular reductants, pH and pO2 shifts, transition metals, thiols, and light denitrosylate

Nitrosylation/denitrosylation during FAS-induced apoptosis

Regulation of signal transduction by coordinated nitrosylation/denitrosylation of proteins is well exemplified in the Fas signaling pathway. Fas is a member of the tumor necrosis factor receptor superfamily that induces apoptosis when ligated. Fas-induced apoptosis is executed by a family of cysteine proteases called caspases. In resting cells, apoptosis may be inhibited, or at least delayed, by S-nitrosylation of the catalytic site cysteine of a subpopulation of caspases located in

Methods for identifying endogenously nitrosylated proteins

It is likely that there are many as yet unidentified pathways regulated by protein nitrosylation. However, progress in identifying these pathways has been hindered by a lack of sensitive and specific methods to identify endogenously nitrosylated proteins. This problem is due in large part to the lability of S–NO and metal–NO bonds, causing artifactual loss and formation of bonds during sample preparation [12], [23]. In addition, levels of endogenously nitrosylated proteins are at or below the

Aberrant nitrosylation and disease

Given the central importance of phosphorylation in regulating cell life, it is not surprising that abnormal phosphorylation has been found to be a cause and consequence of many human diseases [43]. There are also recent data that aberrant nitrosylation is associated with disease pathogenesis. A decrease in airway S-nitrosothiol (SNO) levels has been reported in both asthma and cystic fibrosis [44], [45], [46]. Endogenous airway SNOs enhance ciliary motility [47], relax airway smooth muscle [48]

Conclusion

Virtually every cell function is regulated by phosphorylation/dephosphorylation of proteins. Whether protein nitrosylation/denitrosylation plays a comparable role in cell biology and signal transduction remains to be determined. Given the intriguing similarities between the two posttranslational modifications, it is tempting to speculate that nitrosylation is the “next” phosphorylation. Both modifications are specific, rapidly reversible, chemically simple and have a ready source of

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