Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 382, Issue 1, Pages 72-80Publisher
ACADEMIC PRESS INC
DOI: 10.1006/abbi.2000.1996
Keywords
protein tyrosine phosphatase; VHR; copper ion; oxidative inactivation; metal ions
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The posttranslational regulation of protein tyrosine phosphatases (PTPs) has been suggested to have a crucial role in maintaining the phosphotyrosine level in cells. Here we examined the regulatory effects of metal ions on human dual-specificity vaccinia H1-related protein tyrosine phosphatase (VHR) in vitro. Among various metal ions examined, Fe3+, Cu2+, Zn2+, and Cd2+ exerted their inactivational effects on VHR, and Cu2+ is the most potent inactivator, The VHR activity inactivated by the metal ions except Cu2+ was significantly restored by EDTA, The efficacy of Cu2+ for the VHR inactivation was about 200-fold more potent than that of H2O2. Cu2+ also inactivated other PTPs including PTP1B and SHP-1. The Cu2+-mediated inactivation at the submicromolar range was eradicated by dithiothreitol treatment. The loss of VHR activity correlated with the decreased [C-14]iodoacetate labeling of active-site cysteine, suggesting that Cu2+ brought about the oxidation of the active-site cysteine, On the contrary, Zn2+ that exerted an inactivational effect at millimolar concentrations appeared not directly linked to the active-site cysteine, as indicated by the fact that [C-14]iodoacetate labeling was unaffected and that the effect of Zn2+ on the Y78F mutant was increased, The reduction potential of VHR was estimated to be -331 mV by utilizing the reversibility of the redox state of VHR, Thus, we conclude that the highly potent Cu2+ inactivation of VHR is a consequence of the oxidation of the active-site cysteine and the mode of Zn2+ inactivation is distinct from that of Cu2+. (C) 2000 Academic Press.
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