Protein S-nitrosylation: purview and parameters

Nitric oxide (NO) is produced enzymatically in most or all cell types and tissues. The modification by NO of prosthetic metals in proteins — in particular, haem iron — was shown to mediate some important effects of NO. Subsequently, it emerged that the addition of an NO group to the thiol side chain of cysteine residues within proteins and peptides, which is designated S-nitrosylation, conveys a large part of the ubiquitous influence of NO on cellular signal transduction.Proteins in most or all functional classes function as substrates for S-nitrosylation in vitro and in vivo, and a growing body of research shows the occurrence and effects of endogenous S-nitrosylation in intact cellular systems.It has become clear that S-nitrosylation and de-nitrosylation are precisely regulated in space and time. The specificity of S-nitrosylation within and between proteins is conferred by structural motifs and allosteric regulators, as well as by interactions between NO synthases and target proteins, which might themselves be modulated by S-nitrosylation. Enzymatic activities that promote S-nitrosylation and de-nitrosylation have been identified, but the mechanisms of dynamic regulation in situ remain largely unexplored.Recent work has revealed new effector mechanisms for S-nitrosylation, including the regulation of protein–protein interactions, subcellular localization of proteins and ubiquitylation-dependent protein degradationS-nitrosylation regulates cellular mechanisms that underlie a wide range of critical functions including apoptosis, cellular metabolism, membrane trafficking, protein phosphorylation, the activity of enzymes through both allosteric and active-site modification, transcription-factor stability and activity, receptor-coupled and other ion-channel activity, and maintenance of cellular redox equilibrium (responses to oxidative and nitrosative stress).The elucidation of the physiological roles of S-nitrosylation has begun to impact on the understanding of human health and disease, and the dysregulation of S-nitrosylation is associated with a growing list of pathophysiological conditions (endotoxic shock, multiple sclerosis, Parkinson's disease, pulmonary hypertension, sickle cell disease and asthma).