title: Regulation of the catalytic activity of the human phosphatase PTPN4 by its PDZ domain.
abstract: The human protein tyrosine phosphatase non-receptor type 4 (PTPN4) prevents cells death. Targeting its PDZ domain abrogates this protection and triggers apoptosis. We demonstrate here that the PDZ domain inhibits the phosphatase activity of PTPN4. The mere binding of a PDZ ligand is sufficient to release the catalytic inhibition. We combined analytical ultracentrifugation, small angle X-ray scattering and NMR to understand how the PDZ domain controls PTPN4 activity. We show that the physiologically active PTPN4 two-domain, encompassing the PDZ and the phosphatase domains, adopts a predominant compact conformation in solution. The PDZ ligand binding restores the catalytic competence of PTPN4 disrupting the transient interdomain communication. This study strengthens the emerging notion that PDZ domains can act as regulators of enzyme activity and therefore are active players in the dynamic regulation of signaling pathways.
authors.affiliation: Département de Biologie Structurale et Chimie, Unité de Résonance Magnétique Nucléaire des Biomolécules, Institut Pasteur, Paris, France; Université Pierre et Marie Curie, Cellule Pasteur UPMC, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Maisonneuve
authors.forename: Célia
authors.initials: C
authors.lastname: Caillet-Saguy
authors.forename: Bertrand
authors.initials: B
authors.lastname: Raynal
authors.forename: Bernard
authors.initials: B
authors.lastname: Gilquin
authors.forename: Alain
authors.initials: A
authors.lastname: Chaffotte
authors.forename: Javier
authors.initials: J
authors.lastname: Pérez
authors.forename: Sophie
authors.initials: S
authors.lastname: Zinn-Justin
authors.forename: Muriel
authors.initials: M
authors.lastname: Delepierre
authors.forename: Henri
authors.initials: H
authors.lastname: Buc
authors.forename: Florence
authors.initials: F
authors.lastname: Cordier
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wolff
mesh_terms: D002384:Catalysis; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D054731:PDZ Domains; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D053838:Scattering, Small Angle; D015398:Signal Transduction; D012996:Solutions; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D008024:Ligands; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D012996:Solutions; C516658:PTPN4 protein, human; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4
keywords: PDZ domain; enzymology; intramolecular regulation; protein dynamics; protein tyrosine phosphatase