SAP couples Fyn to SLAM immune receptors

Betty Chan, Arpad Lanyi, Hyun Kyu Song, Jan Griesbach, Maria Simarro-Grande, Florence Poy, Duncan Howie, Janos Sumegi, Cox Terhorst, Michael J. Eck

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226 Scopus citations

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)1-3. 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 blinds to the SH3 domain of FynT and directly couple 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 in teractions. 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.

Original languageEnglish (US)
Pages (from-to)155-160
Number of pages6
JournalNature Cell Biology
Volume5
Issue number2
DOIs
Publication statusPublished - Feb 1 2003

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Chan, B., Lanyi, A., Song, H. K., Griesbach, J., Simarro-Grande, M., Poy, F., ... Eck, M. J. (2003). SAP couples Fyn to SLAM immune receptors. Nature Cell Biology, 5(2), 155-160. https://doi.org/10.1038/ncb920