Mechanism of Protein S-Nitrosylation Regulation

Protein S-nitrosylation refers to the covalent modification of cysteine thiol groups (–SH) by a nitrosyl group (–NO), facilitated by nitric oxide (NO), forming S-nitrosothiols. This reversible post-translational modification is crucial for intracellular signaling, protein function regulation, and numerous pathophysiological processes. In recent years, S-nitrosylation has drawn increasing attention as a key regulatory mechanism, especially in oxidative stress-related diseases like cardiovascular and neurodegenerative disorders, with significant advancements in research on its regulatory mechanisms.

 

Mechanisms of S-Nitrosylation

S-nitrosylation occurs in response to NO production and distribution within cells, primarily catalyzed by nitric oxide synthases (NOS). The following are the critical steps involved in this process:

 

1. NO Synthesis and Diffusion

Nitric oxide is primarily synthesized in cells by three isoforms of NOS: endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS). The synthesized NO can diffuse freely across cellular membranes, reaching different cells and subcellular compartments. It then reacts with target protein cysteine residues via multiple pathways. The short half-life of NO enables it to quickly engage in signal transduction and cellular regulation.

 

2. Selectivity of Target Proteins

S-nitrosylation is highly selective, and not all cysteine residues undergo this modification. Selectivity is influenced by factors such as the subcellular localization of proteins, their tertiary structure, local NO concentration, and the nucleophilicity of cysteine residues. Moreover, the interaction between proteins and low-molecular-weight thiols like glutathione can affect the reversibility and stability of S-nitrosylation.

 

3. Reversibility and Denitrosylation

S-nitrosylation is a reversible modification. Proteins can return to their unmodified states through the process of denitrosylation. The major denitrosylation enzymes include thioredoxin (Trx) and glutathione reductase (GR), which catalyze the reduction of S-nitrosothiols, thereby restoring the unmodified form of proteins and regulating their function and signaling.

 

Physiological Functions of S-Nitrosylation

As an important post-translational modification, S-nitrosylation is involved in various physiological processes such as cell growth, apoptosis, immune response, and metabolic regulation. It can influence protein activity, stability, and protein-protein interactions, thereby affecting cellular signaling pathways. Aberrant S-nitrosylation has been linked to numerous diseases, including atherosclerosis, diabetes, Parkinson's disease, and Alzheimer's disease.

 

Protein S-nitrosylation plays a central role in regulating cellular signaling pathways and has profound implications for both physiological and pathological processes. As our understanding of this modification deepens, it holds great potential for the diagnosis and treatment of diseases associated with S-nitrosylation abnormalities.