Specificity in S-Nitrosylation: A Short-Range Mechanism for NO Signaling?

Abstract

Significance: Nitric oxide (NO) classical and less classical signaling mechanisms (through interaction with soluble guanylate cyclase and cytochrome c oxidase, respectively) operate through direct binding of NO to protein metal centers, and rely on diffusibility of the NO molecule. S-Nitrosylation, a covalent post-translational modification of protein cysteines, has emerged as a paradigm of nonclassical NO signaling. Recent Advances: Several nonenzymatic mechanisms for S-nitrosylation formation and destruction have been described. Enzymatic mechanisms for transnitrosylation and denitrosylation have been also studied as regulators of the modification of specific subsets of proteins. The advancement of modification-specific proteomic methodologies has allowed progress in the study of diverse S-nitrosoproteomes, raising clues and questions about the parameters for determining the protein specificity of the modification. Critical Issues: We propose that S-nitrosylation is mainly a short-range mechanism of NO signaling, exerted in a relatively limited range of action around the NO sources, and tightly related to the very controlled regulation of subcellular localization of nitric oxide synthases. We review the nonenzymatic and enzymatic mechanisms that support this concept, as well as physiological examples of mammalian systems that illustrate well the precise compartmentalization of S-nitrosylation. Future Directions: Individual and proteomic studies of protein S-nitrosylation-based signaling should take into account the subcellular localization in order to gain further insight into the functional role of this modification in (patho)physiological settings.

Nitric oxide negatively regulates abscisic acid signaling in guard cells by S-nitrosylation of OST1

“…The kinase activity of S-nitrosylated SnRK2.6 may be resumed quickly, depending on cellular redox homeostasis. Protein S-nitrosylation depends on the proximity of the protein to NO sources, and on factors for transnitrosylation and denitrosylation, such as thioredoxin and glutathione levels (50). The reversible inhibition of SnRK2 by S-nitrosylation may fine-tune the strength or duration of SnRK2.6 activation in response to ABA.…”

Global Analysis of S-nitrosylation Sites in the Wild Type (APP) Transgenic Mouse Brain-Clues for Synaptic Pathology

“…Viable mitochondria for production of ATP and active energy metabolism, are also present in synaptosomes (88). Moreover, it has recently been proposed that S-nitrosylation is effectively dependent on the subcellular localization of proteins, with short-range linkage to synaptic transmission in neurons (89). Therefore, in order to reduce the complexity of the analyzed system we decided to narrow our studies to proteins involved in synaptic functions, employing fresh synaptosomal preparations routinely used for proteomic screening of affected pathways in the brain (90,91).…”

Redox balance and cardioprotection

“…The de-nitrosylation was firstly considered as a spontaneous and nonregulated process. Recently several non-enzymatic and enzymatic mechanisms of de-nitrosylation have been described in vitro and in vivo [for reviews see [133,138,205,210] (see also below for the role of SNO in cardioprotection).…”