Peptides Targeting the PDZ Domain of PTPN4 Are Efficient Inducers of Glioblastoma Cell Death

• Published in: Structure (London) 2011-10, Vol.19 (10), p.1518-1524
• Main Authors: Babault, Nicolas, Cordier, Florence, Lafage, Mireille, Cockburn, Joseph, Haouz, Ahmed, Prehaud, Christophe, Rey, Félix A., Delepierre, Muriel, Buc, Henri, Lafon, Monique, Wolff, Nicolas
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Biochemistry, Molecular Biology; Cell Death; Cell Line, Tumor; Flow Cytometry; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Life Sciences; Magnetic Resonance Spectroscopy; Molecular Sequence Data; Multiprotein Complexes - metabolism; PDZ Domains; Peptides - pharmacology; Point Mutation; Protein Binding; Protein Structure, Secondary; Protein Tyrosine Phosphatase, Non-Receptor Type 4 - metabolism; Rabies virus - chemistry; Receptors, N-Methyl-D-Aspartate - metabolism; Sequence Alignment; Structural Biology; Viral Proteins - chemical synthesis; Viral Proteins - pharmacology
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2011.07.007

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. ► The structures of PTPN4-PDZ complexed to viral and endogenous peptides are reported ► Slight changes in the PDZ/viral ligands contacts lead to drastic functional effect ► The killing efficiency of peptides closely reflects their affinities for the PDZ ► The best optimized sequence for PTPN4-PDZ binding is the best inducer of cell death