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Protein tyrosine phosphatases PTP-SL and PTPBR7 are isoforms belonging to cytosolic membrane-associated and to receptor-like PTPs (RPTPs), respectively. They represent a new family of PTPs with a major role in activation and translocation of MAP kinases. Specifically, the complex formation between PTP-SL and ERK2 involves an unusual interaction leading to the phosphorylation of PTP-SL by ERK2 at Thr253 and the inactivating dephosphorylation of ERK2 by PTP-SL. This interaction is strictly dependent upon a kinase interaction motif (KIM) (residues 224-239) situated at the N terminus of the PTP-SL catalytic domain. We report the first crystal structure of the catalytic domain for a member of this family (PTP-SL, residues 254-549, identical with residues 361-656 of PTPBR7), providing an example of an RPTP with single cytoplasmic domain, which is monomeric, having an unhindered catalytic site. In addition to the characteristic PTP-core structure, PTP-SL has an N-terminal helix, possibly orienting the KIM motif upon interaction with the target ERK2. An unusual residue in the catalytically important WPD loop promotes formation of a hydrophobically and electrostatically stabilised clamp. This could induce increased rigidity to the WPD loop and therefore reduced catalytic activity, in agreement with our kinetic measurements. A docking model based on the PTP-SL structure suggests that, in the complex with ERK2, the phosphorylation of PTP-SL should be accomplished first. The subsequent dephosphorylation of ERK2 seems to be possible only if a conformational rearrangement of the two interacting partners takes place.

Original publication

DOI

10.1006/jmbi.2001.4890

Type

Journal article

Journal

J Mol Biol

Publication Date

17/08/2001

Volume

311

Pages

557 - 568

Keywords

Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, Catalytic Domain, Crystallography, X-Ray, Humans, Intracellular Signaling Peptides and Proteins, Kinetics, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, Models, Molecular, Molecular Sequence Data, Nerve Tissue Proteins, Phosphorylation, Pliability, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Tyrosine Phosphatases, Receptor-Like Protein Tyrosine Phosphatases, Class 7, Sequence Alignment, Static Electricity, Structure-Activity Relationship