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Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B


Protein tyrosine phosphatases regulate signal transduction pathways involving tyrosine phosphorylation1 and have been implicated in the development of cancer, diabetes, rheumatoid arthritis and hypertension2. Increasing evidence suggests that the cellular redox state is involved in regulating tyrosine phosphatase activity through the reversible oxidization of the catalytic cysteine to sulphenic acid (Cys-SOH)3,4,5,6. But how further oxidation to the irreversible sulphinic (Cys-SO2H) and sulphonic (Cys-SO3H) forms is prevented remains unclear. Here we report the crystal structures of the regulatory sulphenic and irreversible sulphinic and sulphonic acids of protein tyrosine phosphatase 1B (PTP1B), an important enzyme in the negative regulation of the insulin receptor7,8 and a therapeutic target in type II diabetes and obesity9. We also identify a sulphenyl-amide species that is formed through oxidation of its catalytic cysteine. Formation of the sulphenyl-amide causes large changes in the PTP1B active site, which are reversible by reduction with the cellular reducing agent glutathione. The sulphenyl-amide is a protective intermediate in the oxidative inhibition of PTP1B. In addition, it may facilitate reactivation of PTP1B by biological thiols and signal a unique state of the protein.

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Figure 1: Comparison of native and sulphenyl-amide PTP1B.
Figure 2: Putative mechanism of sulphenyl-amide formation and subsequent reactivation.
Figure 3: Different oxidation states of the catalytic cysteine.


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We thank N. Wallis and G. Williams for discussions; O. Callaghan for compounds; I. Tickle for assistance with crystallographic software; and D. Barford for access to his data before submission and for discussions.

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Correspondence to Harren Jhoti.

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The authors declare that they have no competing financial interests.

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van Montfort, R., Congreve, M., Tisi, D. et al. Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B. Nature 423, 773–777 (2003).

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