Regulation of PTP1B via glutathionylation of the active site cysteine 215

William C. Barrett, Jon P. DeGnore, Simone König, Henry M. Fales, Yen Fang Keng, Zhong-Yin Zhang, Moon B. Yim, P. Boon Chock

Research output: Contribution to journalArticle

397 Citations (Scopus)

Abstract

The reversible regulation of protein tyrosine phosphatase is an important mechanism in processing signal transduction and regulating cell cycle. Recent reports have shown that the active site cysteine residue, Cys215, can be reversibly oxidized to a cysteine sulfenic derivative (Denu and Tanner, 1998; Lee et al., 1998). We propose an additional modification that has implications for the in vivo regulation of protein tyrosine phosphatase 1B (PTP1B, EC 3.1.3.48): the glutathionylation of Cys215 to a mixed protein disulfide. Treatment of PTP1B with diamide and reduced glutathione or with only glutathione disulfide (GSSG) results in a modification detected by mass spectrometry in which the cysteine residues are oxidized to mixed disulfides with glutathione. The activity is recovered by the addition of dithiothreitol, presumably by reducing the cysteine disulfides. In addition, inactivated PTP1B is reactivated enzymatically by the glutathione-specific dethiolase enzyme thioltransferase (glutaredoxin), indicating that the inactivated form of the phosphatase is a glutathionyl mixed disulfide. The cysteine sulfenic derivative can easily oxidize to its irreversible sulfinic and sulfonic forms and hinder the regulatory efficiency if it is not converted to a more stable and reversible end product such as a glutathionyl derivative. Glutathionylation of the cysteine sulfenic derivative will prevent the enzyme from further oxidation to its irreversible forms, and constitutes an efficient regulatory mechanism.

Original languageEnglish (US)
Pages (from-to)6699-6705
Number of pages7
JournalBiochemistry
Volume38
Issue number20
DOIs
StatePublished - May 18 1999
Externally publishedYes

Fingerprint

Cysteine
Catalytic Domain
Disulfides
Glutathione Disulfide
Glutaredoxins
Derivatives
Glutathione
Non-Receptor Type 1 Protein Tyrosine Phosphatase
Diamide
Signal transduction
Protein Tyrosine Phosphatases
Dithiothreitol
Enzymes
Phosphoric Monoester Hydrolases
Mass spectrometry
Signal Transduction
Mass Spectrometry
Cell Cycle
Cells
Oxidation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Barrett, W. C., DeGnore, J. P., König, S., Fales, H. M., Keng, Y. F., Zhang, Z-Y., ... Chock, P. B. (1999). Regulation of PTP1B via glutathionylation of the active site cysteine 215. Biochemistry, 38(20), 6699-6705. https://doi.org/10.1021/bi990240v

Regulation of PTP1B via glutathionylation of the active site cysteine 215. / Barrett, William C.; DeGnore, Jon P.; König, Simone; Fales, Henry M.; Keng, Yen Fang; Zhang, Zhong-Yin; Yim, Moon B.; Chock, P. Boon.

In: Biochemistry, Vol. 38, No. 20, 18.05.1999, p. 6699-6705.

Research output: Contribution to journalArticle

Barrett, WC, DeGnore, JP, König, S, Fales, HM, Keng, YF, Zhang, Z-Y, Yim, MB & Chock, PB 1999, 'Regulation of PTP1B via glutathionylation of the active site cysteine 215', Biochemistry, vol. 38, no. 20, pp. 6699-6705. https://doi.org/10.1021/bi990240v
Barrett WC, DeGnore JP, König S, Fales HM, Keng YF, Zhang Z-Y et al. Regulation of PTP1B via glutathionylation of the active site cysteine 215. Biochemistry. 1999 May 18;38(20):6699-6705. https://doi.org/10.1021/bi990240v
Barrett, William C. ; DeGnore, Jon P. ; König, Simone ; Fales, Henry M. ; Keng, Yen Fang ; Zhang, Zhong-Yin ; Yim, Moon B. ; Chock, P. Boon. / Regulation of PTP1B via glutathionylation of the active site cysteine 215. In: Biochemistry. 1999 ; Vol. 38, No. 20. pp. 6699-6705.
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