title: Peptides targeting the PDZ domain of PTPN4 are efficient inducers of glioblastoma cell death.
abstract: PTPN4, a human tyrosine phosphatase, protects cells against apoptosis. This protection could be abrogated by targeting the PDZ domain of this phosphatase with a peptide mimicking the C-terminal sequence of the G protein of an attenuated rabies virus strain. Here, we demonstrate that glioblastoma death is triggered upon intracellular delivery of peptides, either from viral origin or from known endogenous ligands of PTPN4-PDZ, such as the C terminus sequence of the glutamate receptor subunit GluN2A. The killing efficiency of peptides closely reflects their affinities for the PTPN4-PDZ. The crystal structures of two PTPN4-PDZ/peptide complexes allow us to pinpoint the main structural determinants of binding and to synthesize a peptide of high affinity for PTPN4-PDZ enhancing markedly its cell death capacity. These results allow us to propose a potential mechanism for the efficiency of peptides and provide a target and a robust framework for the design of new pro-death compounds.
authors: Unité de Résonance Magnétique Nucléaire des Biomolécules, Département de Biologie Structurale et Chimie, Institut Pasteur, F-75724 Paris, France.
authors: Nicolas
authors: N
authors: Babault
authors: Florence
authors: F
authors: Cordier
authors: Mireille
authors: M
authors: Lafage
authors: Joseph
authors: J
authors: Cockburn
authors: Ahmed
authors: A
authors: Haouz
authors: Christophe
authors: C
authors: Prehaud
authors: Félix A
authors: FA
authors: Rey
authors: Muriel
authors: M
authors: Delepierre
authors: Henri
authors: H
authors: Buc
authors: Monique
authors: M
authors: Lafon
authors: Nicolas
authors: N
authors: Wolff
mesh_terms: D000595:Amino Acid Sequence; D016923:Cell Death; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D054731:PDZ Domains; D010455:Peptides / Q000494:pharmacology*; D017354:Point Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4 / Q000378:metabolism*; D011820:Rabies virus / Q000737:chemistry; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D016415:Sequence Alignment; D014764:Viral Proteins / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D046912:Multiprotein Complexes; D010455:Peptides; D054590:Protein Tyrosine Phosphatase, Non-Receptor Type 4; D016194:Receptors, N-Methyl-D-Aspartate; D014764:Viral Proteins; C516658:PTPN4 protein, human