CRYSTAL-STRUCTURES OF PEPTIDE COMPLEXES OF THE AMINO-TERMINAL SH2 DOMAIN OF THE SYP TYROSINE PHOSPHATASE

Background: Src homology 2 (SH2) domains bind to phosphotyrosine resid ues in a sequence-specific manner, and thereby couple tyrosine phospho rylation to changes in the localization or catalytic activity of signa l transducing molecules. Current understanding of SH2 specificity is b ased on the structures of SH2-peptide complexes of the closely-related Src and Lck tyrosine kinases. The tyrosine phosphatase Syp contains t wo SH2 domains that are relatively divergent from those of the tyrosin e kinases, with distinct target specificities, and is thus well suited for structural studies aimed at extending our understanding of SH2 sp ecificity. Results: Crystal structures of the amino-terminal SH2 domai n of Syp in separate complexes with two high-affinity peptides, in com plex with a non-specific peptide and in the uncomplexed form have been determined at between 2 angstrom and 3 angstrom resolution. The struc ture of the SH2 domain and the mode of high-affinity peptide binding i s essentially similar to that seen in the Src and Lck structures. Howe ver, the binding interface is more extensive in Syp. Conclusions: Most SH2 targets have hydrophobic residues at the third position following the phosphotyrosine, and the Syp structure confirms that the peptide is anchored to the SH2 surface by this residue and by the phosphotyros ine. In addition, the Syp structure has revealed that sequence specifi city can extend across the five residues following the phosphotyrosine , and has shown how the SH2 domain's surface topography can be altered with resulting changes in specificity, while conserving the structure of the central core of the domain.