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Spatial constraints on the recognition of phosphoproteins by the tandem SH2 domains of the phosphatase SH-PTP2

Nature volume 379, pages 277–280 (1996)Cite this article

Abstract

THE domain organization of many signalling proteins facilitates a segregation of binding, catalytic and regulatory functions1,2. The mammalian SH2 domain protein tyrosine phosphatases (PTPs) contain tandem SH2 domains and a single carboxy-terminal catalytic domain3. SH-PTP1 (PTP1C, HCP) and SH-PTP2 (Syp, PTP2C, PTP1D) function downstream from tyrosine kinase-Iinked insulin, growth factor, cytokine and antigen receptors4–12. As well as directing subcellular localization by binding to receptors and their substrates, the two SH2 domains of these PTPs function together to regulate catalysis7,13,14. Here we report the structure of the tandem SH2 domains of SH-PTP2 in complex with monophosphopeptides. A fixed relative orientation of the two domains, stabilized by a disulphide bond and a small hydrophobic patch within the interface, separates the peptide binding sites by ~ 40 Å. The defined orientation of the SH2 domains in the structure, and data showing that peptide orientation and spacing between binding sites is critical for enzymatic activation, suggest that spatial constraints are important in this multidomain protein–protein interaction.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Stephen C. Harrison

  2. Laboratory of Molecular Medicine, Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Michael J. Eck & Stephen C. Harrison

  3. Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Scott Pluskey, Thomas Trüb & Steven E. Shoelson

  4. Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Michael J. Eck, Scott Pluskey, Thomas Trüb & Steven E. Shoelson

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  1. Michael J. Eck
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  4. Stephen C. Harrison
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  5. Steven E. Shoelson
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Eck, M., Pluskey, S., Trüb, T. et al. Spatial constraints on the recognition of phosphoproteins by the tandem SH2 domains of the phosphatase SH-PTP2. Nature 379, 277–280 (1996). https://doi.org/10.1038/379277a0

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