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J. Biol. Chem., Vol. 281, Issue 26, 18236-18245, June 30, 2006

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The Phosphotyrosine Peptide Binding Specificity of Nck1 and Nck2 Src Homology 2 Domains^*

Susanne Frese, Wolf-Dieter Schubert, Antje C. Findeis, Tobias Marquardt, Yvette S. Roske^¶||, Theresia E. B. Stradal¹, and Dirk W. Heinz²

From the German Research Center for Biotechnology, D-38124 Braunschweig, Germany, Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen, Switzerland, ^¶Protein Structure Factory, D-14059 Berlin, Germany, and ^||Max-Delbrück-Centrum für Molekulare Medizin, D-13092 Berlin, Germany

Nck proteins are essential Src homology (SH) 2 and SH3 domain-bearing adapters that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. Two mammalian pathogens, enteropathogenic Escherichia coli and vaccinia virus, exploit Nck as part of their infection strategy. Conflicting data indicate potential differences in the recognition specificities of the SH2 domains of the isoproteins Nck1 (Nck) and Nck2 (Nck and Grb4). We have characterized the binding specificities of both SH2 domains and find them to be essentially indistinguishable. Crystal structures of both domains in complex with phosphopeptides derived from the enteropathogenic E. coli protein Tir concur in identifying highly conserved, specific recognition of the phosphopeptide. Differential peptide recognition can therefore not account for the preference of either Nck in particular signaling pathways. Binding studies using sequentially mutated, high affinity phosphopeptides establish the sequence variability tolerated in peptide recognition. Based on this binding motif, we identify potential new binding partners of Nck1 and Nck2 and confirm this experimentally for the Arf-GAP GIT1.

Received for publication, December 2, 2005 , and in revised form, March 20, 2006.

The atomic coordinates and structure factors (code 2CI8, 2CI9, and 2CIA) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by Deutsche Forschungsgemeinschaft Grant SPP1150 (to T. E. B. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ To whom correspondence may be addressed: Division of Cell Biology, Mascheroder Weg 1, 38124 Braunschweig, Germany. Tel.: 49-531-6181-442; Fax: 49-531-6181-444; E-mail: ths{at}gbf.de. ² To whom correspondence may be addressed: Division of Structural Biology, Mascheroder Weg 1, 38124 Braunschweig, Germany. Tel.: 49-531-6181-766; Fax: 49-531-6181-763; E-mail: dih{at}gbf.de.

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