Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate
Abstract
The second messenger hydrogen peroxide is required for optimal activation of numerous signal transduction pathways, particularly those mediated by protein tyrosine kinases. One mechanism by which hydrogen peroxide regulates cellular processes is the transient inhibition of protein tyrosine phosphatases through the reversible oxidization of their catalytic cysteine, which suppresses protein dephosphorylation. Here we describe a structural analysis of the redox-dependent regulation of protein tyrosine phosphatase 1B (PTP1B), which is reversibly inhibited by oxidation after cells are stimulated with insulin and epidermal growth factor. The sulphenic acid intermediate produced in response to PTP1B oxidation is rapidly converted into a previously unknown sulphenyl-amide species, in which the sulphur atom of the catalytic cysteine is covalently linked to the main chain nitrogen of an adjacent residue. Oxidation of PTP1B to the sulphenyl-amide form is accompanied by large conformational changes in the catalytic site that inhibit substrate binding. We propose that this unusual protein modification both protects the active-site cysteine residue of PTP1B from irreversible oxidation to sulphonic acid and permits redox regulation of the enzyme by promoting its reversible reduction by thiols.
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Hyperactivation of PI3K/Akt/mTOR oxidizes and inactivates the phosphatases PTEN and PTP1B.
“Hyperactivation of PI3K/Akt/mTOR oxidizes and inactivates the phosphatases PTEN and PTP1B (Salmeen et al. 2003).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Salmeen et al. 2003
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- Authors
- Salmeen, A., Andersen, J. N., Myers, M. P., Meng, T.-C., Hinks, J. A., Tonks, N. K., & Barford, D.
- Affiliations
- Institute of Cancer Research (GB)
- Cold Spring Harbor Laboratory (US)
- Corresponding author
- Barford, David
- Venue
- Nature
- Published
- 2003-06
- Volume
- 423
- Issue
- 6941
- Pages
- 769-773
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2109734459
- Cited by
- 951
- References
- 26
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 32 · 2023: 40 · 2022: 32 · 2021: 27 · 2020: 30 · 2019: 37 · 2018: 31 · 2017: 41 · 2016: 31 · 2015: 43 · 2014: 42 · 2013: 63 · 2012: 46
- FWCI
- 18.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Cancer Research UK
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- PTP1B, redox regulation, hydrogen peroxide, protein dephosphorylation, insulin signaling, epidermal growth factor, conformational change, substrate binding, thiol reduction, protein oxidation
- MeSH terms
- Amides, Binding Sites, Cysteine, Epidermal Growth Factor, Insulin, Models, Molecular, Oxidation-Reduction, Phosphorylation, Protein Binding, Protein Conformation, Receptor, Insulin, Serine, Sulfenic Acids, Protein Tyrosine Phosphatases, Amino Acid Substitution, Protein Tyrosine Phosphatase, Non-Receptor Type 1
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