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Protein S-nitrosylation: purview and parameters

Key Points

  • 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 degradation

  • S-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).

Abstract

S-nitrosylation, the covalent attachment of a nitrogen monoxide group to the thiol side chain of cysteine, has emerged as an important mechanism for dynamic, post-translational regulation of most or all main classes of protein. S-nitrosylation thereby conveys a large part of the ubiquitous influence of nitric oxide (NO) on cellular signal transduction, and provides a mechanism for redox-based physiological regulation.

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Figure 1: Cellular sources and targets of nitric oxide.
Figure 2: Concerted acid–base catalysis of protein transnitrosylation.
Figure 3: Regulation by S-nitrosylation of protein–protein interactions of caspase-3.
Figure 4: Regulation of apoptosis through TRX–ASK1 and preservation of the redox equilibrium.
Figure 5: Regulation of signal transduction through Src by S-nitrosylation at multiple loci.
Figure 6: Regulation by S-nitrosylation of protein ubiquitylation and proteasomal targeting.

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Correspondence to Jonathan S. Stamler.

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Competing interests

Dr Stamler and Dr Matsumoto are inventors on patents that concern NO biology, and Dr Stamler is involved in development of NO-based technologies.

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DATABASES

Swiss-Prot

ASK1

CAPON

caspase-3

caspase-8

caspase-9

Dexras1

eNOS

HDM2

HIF1α

HIF2α

IKKα

IKKβ

IKKγ

iNOS

IRP1

IRP2

JNK1

JNK3

MKK3

MKK6

MMP9

nNOS

OxyR

p21Ras

p53

p60Src

PSD95

RyR1

RyR2

SOD

TACE

TNFα

TRX

FURTHER INFORMATION

eMOTIF

Glossary

NO SYNTHASE

(NOS). Mammals have three NO synthases that generate NO from Arg — NOS1 or nNOS, NOS2 or iNOS and NOS3 or eNOS — one or more of which reside, or can be induced, in most or all cell types. NOS homologues are distributed broadly across the phylogeny.

S-NITROSO-GLUTATHIONE

(GSNO). The main non-protein S-nitrosothiol (SNO) in cells, which functions in an equilibrium with protein SNOs (the equilibrium is determined in part by the enzyme GSNO-reductase, which metabolizes GSNO (see Table 1)).

OXIDOREDUCTASE

An enzyme that catalyses oxidation–reduction reactions, which entail the transfer of electrons from a substrate that becomes oxidized (electron donor) to a substrate that becomes reduced (electron acceptor).

NITROSATIVE AND OXIDATIVE STRESS

The dysregulated production and/or metabolism of reactive nitrogen and/or oxygen species, which generate nitrosative and/or oxidative chemistries that can result in disrupted cellular signalling, injury and death.

NUCLEOPHILICITY

Nucleophilic groups such as the sulphur group of Cys are electron rich, and the degree of nucleophilicity is a measure of their reactivity towards electrophiles (electron-deficient species such as NO+), as exemplified by the increased reactivity of cysteine thiolate versus sulfhydryl.

ALLOSTERIC REGULATOR

An ion or small molecule that reacts with and thereby modulates the conformation and function of proteins. A number of such allosteric regulators, including O2 and Ca2+, have been implicated in the regulation of protein S-nitrosylation.

METALLOPROTEIN

A protein that contains a metal ion (or ions; such as Fe2+, Cu2+ or Zn2+) as a prosthetic group, which is coordinated by amino-acid side chains.

TAUTOMERIC

Describes the relationship between two structural isomers of a molecule that are in chemical equilibrium, which includes the two forms that result from the intramolecular transfer of an acidic proton.

REACTIVE OXYGEN SPECIES

Reduced derivatives of molecular oxygen (O2), including, in particular, the superoxide radical (O2•−) and hydrogen peroxide (H2O2), which can have significant reactivity towards biological macromolecules and towards other reactive small molecules.

POLYAMINE

A metabolic product of Arg (the substrate for NO synthases), which is generated through a highly regulated sequence of enzymatic reactions.

WEIBEL–PALADE BODY

A secretory vesicle containing agents, including the von Willebrand factor, which are exocytosed from endothelial cells following inflammatory stimulation.

SARCOPLASMIC RETICULUM (SR).

A specialized form of endoplasmic reticulum in muscle cells that sequesters and releases Ca2+ to control muscle contractility.

GSH/GSSG

The ratio of reduced to oxidized (disulphide-linked) glutathione. This ratio is a principal indicator of the redox state of a cell or subcellular compartment.

INOTROPIC

Influencing muscle contractility.

NORMOXIA

Ambient O2 (21%) or, in reference to tissue, O2 concentrations that represent the normal physiological state (2–3%).

LEWIS ACID

An electron-pair acceptor that can participate as one member of a conjugate acid–base pair in acid–base reactions.

METALLOTHIONEIN

A small Cys-rich protein that binds metal ions — in particular, Zn2+ and/or Cu2+ — at least in part, through complex formation with cysteine thiolate.

EXTRACELLULAR MATRIX METALLOPROTEINASE

(MMP). A Zn2+-dependent proteolytic enzyme that has an extracellular active site, which is capable of breaking down extracellular-matrix components.

METALLOPROTEINASE/DISINTEGRIN (ADAM) FAMILY

A family of extracellular metalloproteinases that are implicated in the proteolytic processing of membrane-bound substrates, which results in ectodomain shedding, and are named after their characteristic ADAM-domain structure.

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Hess, D., Matsumoto, A., Kim, SO. et al. Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol 6, 150–166 (2005). https://doi.org/10.1038/nrm1569

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