title: Molecular Basis of the Interaction of the Human Protein Tyrosine Phosphatase Non-receptor Type 4 (PTPN4) with the Mitogen-activated Protein Kinase p38γ.
abstract: The human protein tyrosine phosphatase non-receptor type 4 (PTPN4) prevents cell death induction in neuroblastoma and glioblastoma cell lines in a PDZ·PDZ binding motifs-dependent manner, but the cellular partners of PTPN4 involved in cell protection are unknown. Here, we described the mitogen-activated protein kinase p38γ as a cellular partner of PTPN4. The main contribution to the p38γ·PTPN4 complex formation is the tight interaction between the C terminus of p38γ and the PDZ domain of PTPN4. We solved the crystal structure of the PDZ domain of PTPN4 bound to the p38γ C terminus. We identified the molecular basis of recognition of the C-terminal sequence of p38γ that displays the highest affinity among all endogenous partners of PTPN4. We showed that the p38γ C terminus is also an efficient inducer of cell death after its intracellular delivery. In addition to recruiting the kinase, the binding of the C-terminal sequence of p38γ to PTPN4 abolishes the catalytic autoinhibition of PTPN4 and thus activates the phosphatase, which can efficiently dephosphorylate the activation loop of p38γ. We presume that the p38γ·PTPN4 interaction promotes cellular signaling, preventing cell death induction.
authors.affiliation: From the Département de Biologie Structurale et Chimie, Unité de Résonance Magnétique Nucléaire des Biomolécules, UMR 3528 and Université Pierre et Marie Curie, Cellule Pasteur UPMC, 75005 Paris, France.
authors.forename: Pierre
authors.identifier: 0000-0001-8292-5741
authors.initials: P
authors.lastname: Maisonneuve
authors.affiliation: From the Département de Biologie Structurale et Chimie, Unité de Résonance Magnétique Nucléaire des Biomolécules, UMR 3528 and.
authors.forename: Célia
authors.initials: C
authors.lastname: Caillet-Saguy
authors.affiliation: Unité de Virologie Structurale, Département de Virologie, UMR 3569, CNRS, F-75724 Paris, France, and.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Vaney
authors.affiliation: From the Département de Biologie Structurale et Chimie, Unité de Résonance Magnétique Nucléaire des Biomolécules, UMR 3528 and.
authors.forename: Edoo
authors.initials: E
authors.lastname: Bibi-Zainab
authors.affiliation: From the Département de Biologie Structurale et Chimie, Unité de Résonance Magnétique Nucléaire des Biomolécules, UMR 3528 and.
authors.forename: Kristi
authors.initials: K
authors.lastname: Sawyer
authors.affiliation: UMR 3528 and Plate-Forme de Biophysique des Macromolécules, and.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Raynal
authors.affiliation: UMR 3528 and Plate-Forme de Cristallographie, Institut Pasteur, F-75724 Paris, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Haouz
authors.affiliation: From the Département de Biologie Structurale et Chimie, Unité de Résonance Magnétique Nucléaire des Biomolécules, UMR 3528 and.
authors.forename: Muriel
authors.initials: M
authors.lastname: Delepierre
authors.affiliation: UMR 3569, CNRS, F-75724 Paris, France, and Unité de Neuro-Immunologie Virale, Département de Virologie.
authors.forename: Monique
authors.initials: M
authors.lastname: Lafon
authors.affiliation: From the Département de Biologie Structurale et Chimie, Unité de Résonance Magnétique Nucléaire des Biomolécules, UMR 3528 and.
authors.forename: Florence
authors.initials: F
authors.lastname: Cordier
authors.affiliation: From the Département de Biologie Structurale et Chimie, Unité de Résonance Magnétique Nucléaire des Biomolécules, UMR 3528 and nicolas.wolff@pasteur.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wolff
mesh_terms: D016923:Cell Death; D045744:Cell Line, Tumor; D006801:Humans; D048291:Mitogen-Activated Protein Kinase 12 / Q000235:genetics / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D009097:Multienzyme Complexes; D048291:Mitogen-Activated Protein Kinase 12; C516658:PTPN4 protein, human; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4
keywords: AMP-activated kinase (AMPK); PDZ domain; PTPN4; nuclear magnetic resonance (NMR); p38γ; phosphatase; protein-protein interaction; x-ray crystallography