Structural basis for inhibition of receptor protein-tyrosine phosphatase-α by dimerization

RECEPTOR-LIKE protein-tyrosine phosphatases (RPTPs), like their non-receptor counterparts, regulate the level of phosphotyrosine-containing proteins derived from the action of protein-tyrosine kineses 1 . RPTPs are type-I integral membrane proteins which contain one or two catalytic domains in their cytoplasmic region 2 . It is not known whether extracellular ligands regulate the activity of RPTPs. Here we describe the crystal structure of the membrane-proximal catalytic domain (D1) of a typical RPTP, murine RPTPα. Significant structural deviations from the PTP1B fold reside within the amino-terminal helix–turn–helix segment of RPTPαD1 (residues 214 to 242) and a distinctive two-stranded β-sheet formed between residues 211–213 and 458–461. The turn of the N-terminal segment inserts into the active site of a dyad-related D1 monomer. On the basis of two independent crystal structures, sequence alignments, and the reported biological activity of EGF receptor/CD45 chimaeras 3 , we propose that dimerization and active-site blockage is a physiologically important mechanism for downregulating the catalytic activity of RPTPα and other RPTPs.