Structural basis for substrate specificity of protein-tyrosine phosphatase SHP-1

The substrate specificity of the catalytic domain of SHP-1, an important regulator in the proliferation and development of hematopoietic cells, is critical for understanding the physiological functions of SHP-1, Here we report the crystal structures of the catalytic domain of SHP-1 complexed with two peptide substrates derived from SIRP alpha, a member of the signal-regulatory proteins. We show that the variable beta 6-loop-beta 6 motif confers SHP-1 substrate specificity at the P-4 and further N-terminal subpockets. We also observe a novel residue shift at P-2, the highly conserved subpocket in protein-tyrosine phosphatases, Our observations provide new insight into the substrate specificity of SHP-1.