Discovering mechanisms of signaling-mediated cysteine oxidation

Abstract

SummaryAccumulating evidence reveals hydrogen peroxide as a key player both as a damaging agent and, from emerging evidence over the last decade, as a second messenger in intracellular signaling. This rather mild oxidant acts upon downstream targets within signaling cascades to modulate the activity of a host of enzymes (e.g. phosphatases and kinases) and transcriptional regulators through chemoselective oxidation of cysteine residues. With the recent development of specific detection reagents for hydrogen peroxide and new chemical tools to detect the generation of the initial oxidation product, sulfenic acid, on reactive cysteines within target proteins, the scene is set to gain a better understanding of the mechanisms through which hydrogen peroxide acts as a second messenger in cell signaling.

Ethylene-Induced Flavonol Accumulation in Guard Cells Suppresses Reactive Oxygen Species and Moderates Stomatal Aperture

“…This oxidant, generated from superoxide O 2 .2 molecules, can modulate the activity of phosphatases and kinases, causing dynamic changes in signal transduction pathways (Poole et al, 2004). Specifically, H 2 O 2 can interact with specific Cys residues, transforming the functional group of the Cys into sulfenic acid, altering formation of disulfide bonds between two separate proteins or between nearby Cys residues of the same protein, in a transient, reversible fashion (Poole et al, 2004;Poole and Nelson, 2008). In guard cells, this ROS burst is believed to target calcium channels to promote the influx of calcium across the plasma membrane and the release of calcium from internal stores (McAinsh et al, 1996;Allen et al, 2000;Cho et al, 2009).…”

“…Increased cytosolic calcium levels induce activation of anion efflux channels located on the plasma membrane (Hedrich et al, 1990;Schroeder and Hagiwara, 1990;Chen et al, 2010;Wang et al, 2013), triggering stomatal closure. The mechanism behind ROS activation of Ca 2+ channels in mammalian systems has been well studied (Poole and Nelson, 2008); however, less is known about this mechanism in plants.…”

Multilevel Regulation of 2-Cys Peroxiredoxin Reaction Cycle by S-Nitrosylation

“…There is mounting evidence that biologically relevant reactive oxygen species/reactive nitrogen species, particularly hydrogen peroxide (H 2 O 2 ) and nitric oxide (NO), affect cellular behavior in part through reversible modifications of cysteine residues in proteins. Specifically, H 2 O 2 can react with a cysteine thiol to form a sulfenic acid (SOH), 2 whereas NO promotes the conversion of a thiol to a nitrosothiol (SNO), a process known as S-nitrosylation (or S-nitrosation) (5)(6)(7)(8). Formation of SOH or SNO can in turn give rise to other thiol modifications, including S-glutathionylation or intra/intermolecular disulfide formation.…”

Oxidation-induced intramolecular disulfide bond inactivates mitogen-activated protein kinase kinase 6 by inhibiting ATP binding

“…Oxidative stress is triggered by an imbalanced cellular redox state that is normally tightly regulated by oxidants including reactive oxygen species as well as reactive nitrogen species, and antioxidants including glutathione and thioredoxin (11). Many cellular proteins are known to be directly regulated by the cellular redox state with the thiol group of cysteine (Cys) being a major target for oxidationinduced chemical modification (13,14). Depending on the microenvironment surrounding cysteine residues in a particular tertiary structure of a protein, selected cysteines can be preferentially deprotonated to form thiolate ions that can be readily oxidized to form sulfenic acids or undergo S-nitrosylation.…”

“…Depending on the microenvironment surrounding cysteine residues in a particular tertiary structure of a protein, selected cysteines can be preferentially deprotonated to form thiolate ions that can be readily oxidized to form sulfenic acids or undergo S-nitrosylation. Sulfenic acid is generally unstable and can be either further oxidized to form sulfinic acid and sulfonic acid or converted to a disulfide with another thiol from proteins (i.e., intramolecular or intermolecular disulfide) or small thiol-containing molecules (e.g., glutathione) (11,(13)(14)(15). In addition, sulfenic acid may also be converted to cyclic sulfenamide through the nucleophilic attack of sulfur by a neighboring backbone amide nitrogen (14,16,17).…”