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SAP couples Fyn to SLAM immune receptors

Nature Cell Biology volume 5, pages 155–160 (2003)Cite this article

Abstract

SAP (SLAM-associated protein) is a small lymphocyte-specific signalling molecule that is defective or absent in patients with X-linked lymphoproliferative syndrome (XLP)1,2,3. Consistent with its single src homology 2 (SH2) domain architecture and unusually high affinity for SLAM (also called CD150), SAP has been suggested to function by blocking binding of SHP-2 or other SH2-containing signalling proteins to SLAM receptors1,4. Additionally, SAP has recently been shown to be required for recruitment and activation of the Src-family kinase FynT after SLAM ligation5. This signalling 'adaptor' function has been difficult to conceptualize, because unlike typical SH2-adaptor proteins, SAP contains only a single SH2 domain and lacks other recognized protein interaction domains or motifs. Here, we show that the SAP SH2 domain binds to the SH3 domain of FynT and directly couples FynT to SLAM. The crystal structure of a ternary SLAM–SAP–Fyn-SH3 complex reveals that SAP binds the FynT SH3 domain through a surface–surface interaction that does not involve canonical SH3 or SH2 binding interactions. The observed mode of binding to the Fyn-SH3 domain is expected to preclude the auto-inhibited conformation of Fyn, thereby promoting activation of the kinase after recruitment. These findings broaden our understanding of the functional repertoire of SH3 and SH2 domains.

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Figure 1: SAP couples Fyn to SLAM through the Fyn-SH3 domain.
Figure 2: Structure of the SLAM–SAP–Fyn-SH3 ternary complex.
Figure 3: In vitro binding studies with purified Fyn-SH3 and SAP.
Figure 4: A model for recruitment and activation of Fyn by SAP.

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Acknowledgements

We thank S.J. Freedman for assistance with the ITC experiments and helpful discussions. This work was supported in part by grants from the National Institutes of Health (M.J.E. and C.T.) and the Hungarian Academy of Sciences (A.L.). M.J.E. is a recipient of the Leukaemia and Lymphoma Society Scholar Award. Correspondence and requests for materials should be addressed to M.J.E.

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Author notes

  1. Arpad Lanyi

    Present address: Institute of Immunology, University of Debrecen, H-4012, Hungary

  2. Betty Chan, Arpad Lanyi and Hyun Kyu Song: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, 02115, MA, USA

    Betty Chan, Hyun Kyu Song, Jan Griesbach, Florence Poy & Michael J. Eck

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, 02115, MA, USA

    Betty Chan, Hyun Kyu Song & Michael J. Eck

  3. Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02115, MA, USA

    Arpad Lanyi, Maria Simarro-Grande, Duncan Howie & Cox Terhorst

  4. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, 68198-5660, NE, USA

    Janos Sumegi

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Chan, B., Lanyi, A., Song, H. et al. SAP couples Fyn to SLAM immune receptors. Nat Cell Biol 5, 155–160 (2003). https://doi.org/10.1038/ncb920

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