The structure of the bovine protein tyrosine phosphatase dimer reveals a potential self-regulation mechanism

The bovine protein tyrosine phosphatase (BPTP) is a member of the class of low-molecular weight protein tyrosine phosphatases (PTPases) found to be ub iquitous in mammalian cells. The catalytic site of BPTP contains a CX5R(S/T ) phosphate-binding motif or P-loop (residues 12-19) which is the signature sequence for all PTPases. Ser19, the final residue of the P-loop motif, in teracts with the catalytic Cys12 and participates in stabilizing the confor mation of the active site through interactions with Asn15, also in the P-lo op. Mutations at Ser19 result in an enzyme with altered kinetic properties with changes in the pK(a) of the neighboring His72. The X-ray structure of the S19A mutant enzyme shows that the general conformation of the P-loop is preserved. However, changes in the loop containing His72 result in a displ acement of the His72 side chain that may explain the shift in the pK(a). In addition, it was found that in the crystal, the protein forms a dimer in w hich Tyr131 and Tyr132 from one monomer insert into the active site of the other monomer, suggesting a dual-tyrosine motif on target sites for this en zyme. Since the activity of this PTPase is reportedly regulated by phosphor ylation at Tyr131 and Tyr132, the structure of this dimer may provide a mod el of a self-regulation mechanism for the low-molecular weight PTPases.