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Originally published In Press as doi:10.1074/jbc.M011185200 on February 2, 2001

J. Biol. Chem., Vol. 276, Issue 20, 17199-17205, May 18, 2001
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The Role of the Src Homology 3-Src Homology 2 Interface in the Regulation of Src Kinases*

Stefan T. AroldDagger §, Tobias S. Ulmer, Terrence D. Mulhern||, Jörn M. Werner, John E. Ladbury**Dagger Dagger , Iain D. Campbell§§, and Martin E. M. NobleDagger ¶¶

From the Dagger  Laboratory of Molecular Biophysics and  Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom, ** Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom, and || Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria 3010, Australia

The regulatory fragment of Src kinases, comprising Src homology (SH) 3 and SH2 domains, is responsible for controlled repression of kinase activity. We have used a multidisciplinary approach involving crystallography, NMR, and isothermal titration calorimetry to study the regulatory fragment of Fyn (FynSH32) and its interaction with a physiological activator: a fragment of focal adhesion kinase that contains both phosphotyrosine and polyproline motifs. Although flexible, the preferred disposition of SH3 and SH2 domains in FynSH32 resembles the inactive forms of Hck and Src, differing significantly from LckSH32. This difference, which results from variation in the SH3-SH2 linker sequences, will affect the potential of the regulatory fragments to repress kinase activity. This surprising result implies that the mechanism of repression of Src family members may vary, explaining functional distinctions between Fyn and Lck. The interaction between FynSH32 and focal adhesion kinase is restricted to the canonical SH3 and SH2 binding sites and does not affect the dynamic independence of the two domains. Consequently, the interaction shows no enhancement by an avidity effect. Such an interaction may have evolved to gain specificity through an extended recognition site while maintaining rapid dissociation after signaling.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Fellow of the Medical Research Council.

Dagger Dagger A Wellcome Trust Senior Research Fellow.

§§ Supported by the Wellcome Trust.

¶¶ To whom correspondence should be addressed. E-mail: martin@biop.ox.ac.uk.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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