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Regulation of PTP1B activation through disruption of redox-complex formation

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Abstract

We have identified a molecular interaction between the reversibly oxidized form of protein tyrosine phosphatase 1B (PTP1B) and 14-3-3ζ that regulates PTP1B activity. Destabilizing the transient interaction between 14-3-3ζ and PTP1B prevented PTP1B inactivation by reactive oxygen species and decreased epidermal growth factor receptor phosphorylation. Our data suggest that destabilizing the interaction between 14-3-3ζ and the reversibly oxidized and inactive form of PTP1B may establish a path to PTP1B activation in cells.

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Fig. 1: The exposed pTyr recognition loop of PTP1B-OX interacts with 14-3-3ζ.
Fig. 2: Destabilizing the association between 14-3-3ζ and PTP1B-OX prevents PTP1B inactivation and decreases EGFR phosphorylation.

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Data availability

The structures of reduced PTP1B (PDB code: 2HNQ) and PTP1B-OX (PDB code: 1OEM) were used for the accessible surface area calculation. The MS data in Supplementary Tables 1 and 2 will be made available in the PRoteomics IDEntifications database.

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Acknowledgements

We thank H. Fu for providing the 14-3-3ζ plasmid. This research was supported by the National Institutes of Health grant no. HL138605 and the American Heart Association grant no. 17GRNT33700265 to B.B. and National Institutes of Health grant no. GM55989 to N.K.T. B.B. is also grateful for support from the following foundations: the Heart and Stroke Foundation of Canada and SUNY Research Foundation. B.B. is an FRQS Research Scholar and A.B. was the recipient of a scholarship from the FRQS.

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Author notes

  1. These authors contributed equally: Avinash D. Londhe, Alexandre Bergeron.

Authors and Affiliations

  1. Department of Nanobioscience, College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY, USA

    Avinash D. Londhe, Stephanie M. Curley, Akaash Kannan, Gérald Coulis, Syed H. M. Rizvi & Benoit Boivin

  2. Department of Medicine, Université de Montréal, Montreal, Quebec, Canada

    Alexandre Bergeron & Benoit Boivin

  3. Montreal Heart Institute, Montreal, Quebec, Canada

    Alexandre Bergeron, Gérald Coulis & Benoit Boivin

  4. Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA

    Fuming Zhang & Robert J. Linhardt

  5. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

    Keith D. Rivera, Darryl J. Pappin, Nicholas K. Tonks & Benoit Boivin

  6. Division of Biomedical Sciences, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Korea

    Seung Jun Kim

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  1. Avinash D. Londhe
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Contributions

A.D.L., A.B., S.M.C., A.K., G.C., S.H.M.R. and B.B. performed experiments and analyzed data. K.D.R. and D.J.P. acquired and analyzed MS data. S.J.K. performed structural analysis and modeling. F.Z. and R.J.L. acquired and analyzed SPR data. N.K.T. and B.B. wrote the manuscript.

Corresponding author

Correspondence to Benoit Boivin.

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Supplementary Information

Supplementary Tables 1 and 2 and Figs. 1–21.

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Londhe, A.D., Bergeron, A., Curley, S.M. et al. Regulation of PTP1B activation through disruption of redox-complex formation. Nat Chem Biol 16, 122–125 (2020). https://doi.org/10.1038/s41589-019-0433-0

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