CRYSTAL-STRUCTURE OF HUMAN PROTEIN-TYROSINE-PHOSPHATASE 1B

Protein tyrosine phosphatases (PTPs) constitute a family of receptor-l ike and cytoplasmic signal transducing enzymes that catalyze the depho sphorylation of phosphotyrosine residues and are characterized by homo logous catalytic domains. The crystal structure of a representative me mber of this family, the 37-kilodalton form (residues 1 to 321) of PTP 1 B, has been determined at 2.8 Angstrom resolution. The enzyme consis ts of a single domain with the catalytic site located at the base of a shallow cleft. The phosphate recognition site is created from a loop that is located at the amino-terminus of an or helix. This site is for med from an 11-residue sequence motif that is diagnostic of PTPs and t he dual specificity phosphatases, and that contains the catalytically essential cysteine and arginine residues. The position of the invarian t cysteine residue within the phosphate binding site is consistent wit h its role as a nucleophile in the catalytic reaction. The structure o f PTP1B should serve as a model for other members of the PTP family an d as a framework for understanding the mechanism of tyrosine dephospho rylation.