Structural basis for substrate specificity of protein-tyrosine phosphataseSHP-1

The substrate specificity of the catalytic domain of SHP-1, an important re gulator in the proliferation and development of hematopoietic cells, is cri tical for understanding the physiological functions of SHP-1, Here we repor t the crystal structures of the catalytic domain of SHP-1 complexed with tw o peptide substrates derived from SIRP alpha, a member of the signal-regula tory proteins. We show that the variable beta 6-loop-beta 6 motif confers S HP-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.