Crystal structure of the tandem phosphatase domains of RPTP LAR

Most receptor-like protein tyrosine phosphatases (RPTPs) contain two conser ved phosphatase domains (D1 and D2) in their intracellular region. The carb oxyterminal D2 domain has little or no catalytic activity. The crystal stru cture of the tandem D1 and D2 domains of the human RPTP LAR revealed that t he tertiary structures of the LAR D1 and D2 domains are very similar to eac h other, with the exception of conformational differences at two amino acid positions in the D2 domain. Site-directed mutational changes at these posi tions (Leu-1644-to-Tyr and Glu-1779-to-Asp) conferred a robust PTPase activ ity to the D2 domain. The catalytic sites of both domains are accessible, i n contrast to the dimeric blocked orientation model previously suggested. T he relative orientation of the LAR D1 and D2 domains, constrained by a shor t linker, is stabilized by extensive interdomain interactions, suggesting t hat this orientation might be favored in solution.