Protein tyrosine phosphatase SHP-1 specifically recognizes C-terminal residues of its substrates via helix alpha 0

The catalytic domain of protein tyrosine phosphatase SHP-1 possesses distin ct substrate specificity. It recognizes the P-3 to P-5 residues of its subs trates via the beta5-loop-beta6 region. To study the substrate specificity further, we determined the structure of the catalytic domain of SHP-1 (C455 S) complexed with a less-favorable-substrate peptide originated from SIRP a lpha. The complex has disordered N-terminal peptide structure and reduced i nteractions between the N-terminal peptide and the beta5-loop-beta6 region. This could be the basis for the lower affinity of peptide pY(427) for the catalytic domain of SHP-1. In addition, by comparing the SHP-1/less-favorab le peptide complex structure with the SHP-1 /substrate complex structures, we identified a novel substrate-recognition site in the catalytic domain of SHP-1. This site was formed by helix alpha0 and the alpha5-loop-alpha6 mot if of SHP-1, and specifically bound residues at the P + 4 and further C-ter minal positions of peptide substrates. J. Cell. Biochem. 83: 14-20, 2001. ( C) 2001 Wiley-Liss, Inc.