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J. Biol. Chem., Vol. 281, Issue 29, 20271-20282, July 21, 2006

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Sequence Specificity of SHP-1 and SHP-2 Src Homology 2 Domains

CRITICAL ROLES OF RESIDUES BEYOND THE pY+3 POSITION^*

Diana Imhof¹², Anne-Sophie Wavreille², Andreas May, Martin Zacharias, Susheela Tridandapani^¶, and Dehua Pei³

From the Departments of Chemistry and ^¶Internal Medicine, Ohio State University, Columbus, Ohio 43210 and the School of Engineering and Science, International University Bremen, Campus Ring 1, D-28759 Bremen, Germany

A combinatorial phosphotyrosyl (pY) peptide library was screened to determine the amino acid preferences at the pY+4 to pY+6 positions for the four SH2 domains of protein-tyrosine phosphatases SHP-1 and SHP-2. Individual binding sequences selected from the library were resynthesized and their binding affinities and specificities to various SH2 domains were further evaluated by SPR studies, stimulation of SHP-1 and SHP-2 phosphatase activity, and in vitro pulldown assays. These studies reveal that binding of a pY peptide to the N-SH2 domain of SHP-2 is greatly enhanced by a large hydrophobic residue (Trp, Tyr, Met, or Phe) at the pY+4 and/or pY+5 positions, whereas binding to SHP-1 N-SH2 domain is enhanced by either hydrophobic or positively charged residues (Arg, Lys, or His) at these positions. Similar residues at the pY+4 to pY+6 positions are also preferred by SHP-1 and SHP-2 C-SH2 domains, although their influence on the overall binding affinities is much smaller compared with the N-SH2 domains. A structural model was generated to qualitatively interpret the contribution of the pY+4 and pY+5 residues to the overall binding affinity. Examination of pY motifs from known SHP-1 and SHP-2-binding proteins shows that many of the pY motifs contain a hydrophobic or positively charged residue(s) at the pY+4 and pY+5 positions.

Received for publication, February 3, 2006 , and in revised form, April 6, 2006.

^* This work was supported by National Institutes of Health Grants GM062820 and RR15895. 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.

¹ Present address: Institute of Biochemistry and Biophysics, Friedrich-Schiller-University, Philosophenweg 12, D-07743 Jena, Germany.

² These two authors contributed equally to this work.

³ To whom correspondence should be addressed: Dept. of Chemistry, Ohio State University, 100 W. 18th Ave., Columbus, OH 43210. Tel.: 614-688-4068; Fax: 614-292-1532; E-mail: pei.3{at}osu.edu.

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