Redox Regulation of Protein Tyrosine Phosphatases: Structural and Chemical Aspects

Abstract

Protein tyrosine phosphatases (PTPs) are important targets of the H(2)O(2) that is produced during mammalian signal transduction. H(2)O(2)-mediated inactivation of PTPs also may be important in various pathophysiological conditions involving oxidative stress. Here we review the chemical and structural biology of redox-regulated PTPs. Reactions of H(2)O(2) with PTPs convert the catalytic cysteine thiol to a sulfenic acid. In PTPs, the initially generated sulfenic acid residues have the potential to undergo secondary reactions with a neighboring amide nitrogen or cysteine thiol residue to yield a sulfenyl amide or disulfide, respectively. The chemical mechanisms by which formation of sulfenyl amide and disulfide linkages can protect the catalytic cysteine residue against irreversible overoxidation to sulfinic and sulfonic oxidation states are described. Due to the propensity for back-door and distal cysteine residues to engage with the active-site cysteine after oxidative inactivation, differences in the structures of the oxidatively inactivated PTPs may stem, to a large degree, from differences in the number and location of cysteine residues surrounding the active site of the enzymes. PTPs with key cysteine residues in structurally similar locations may be expected to share similar mechanisms of oxidative inactivation.

Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1

“…When Cys 367 and Cys 333 are oxidized, their physical distance favors the generation of a disulfide bridge between the two of them, protecting the catalytic domain Cys 463 from oxidation (25). In conditions in which one backdoor cysteine is irreversibly oxidized or in a mixed disulfide with another protein or molecule, it is then possible for the free backdoor cysteine to interact directly with the catalytic cysteine, rendering the phosphatase inactive (26). Our findings that s-glutathiolation of Cys 463 was reversible, while that of Cys 333 was not, support this mechanism and suggest that irreversible oxidation of Cys 333 leads the catalytic Cys 463 to be prone to s-glutathiolation.…”

The Redox Biochemistry of Protein Sulfenylation and Sulfinylation

“…Sulfenylation of the catalytic Cys residue (pK a ϭ 4 -6) of PTPs has emerged as a dynamic mechanism for inactivation of this protein family (20). The half-life of RSOH is generally quite low in PTPs.…”

Sulfenome mining in Arabidopsis thaliana

“…The MAPK activity is also controlled through dephosphorylation by redox-sensitive phosphatases (17). Sulfenylation of the catalytic nucleophilic cysteine leads to the inhibition of protein tyrosine phosphatases (PTPs) (19). The identified Arabidopsis AtPTP1 undergoes cysteine-dependent inhibition by H 2 O 2 and negatively regulates the MAPKs (20), suggesting that the oxidation-dependent AtPTP1 inhibition might be a primary step in the oxidative stress response leading to MAPK signaling derepression (21).…”