title: Crystal structure of PTP-SL/PTPBR7 catalytic domain: implications for MAP kinase regulation.
abstract: 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.
authors.affiliation: Department of Enzymology, Institute of Biochemistry, Spl. Independentei 296, Bucharest, 77700, Romania. stefan.szedlacsek@biochim.ro
authors.forename: S E
authors.initials: SE
authors.lastname: Szedlacsek
authors.forename: A R
authors.initials: AR
authors.lastname: Aricescu
authors.forename: T A
authors.initials: TA
authors.lastname: Fulga
authors.forename: L
authors.initials: L
authors.lastname: Renault
authors.forename: A J
authors.initials: AJ
authors.lastname: Scheidig
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D018583:Pliability; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000378:metabolism*; D054634:Receptor-Like Protein Tyrosine Phosphatases, Class 7; D016415:Sequence Alignment; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; C513469:PTPRR protein, human; D017027:Protein Tyrosine Phosphatases; C513472:Ptprr protein, mouse; D054634:Receptor-Like Protein Tyrosine Phosphatases, Class 7