The Sam-Sam interaction between Ship2 and the EphA2 receptor: design and analysis of peptide inhibitors
| Autor: | Luciano Pirone, Emilia Pedone, Rosanna Palumbo, Roberta Iannitti, Concetta Di Natale, Daniela Marasco, Marilisa Leone, Flavia Anna Mercurio |
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| Přispěvatelé: | Mercurio, Flavia Anna, Di Natale, Concetta, Pirone, Luciano, Iannitti, Roberta, Marasco, Daniela, Pedone, Emilia Maria, Palumbo, Rosanna, Leone, Marilisa |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
Models Molecular 0301 basic medicine Saccharomyces cerevisiae Proteins lcsh:Medicine Antineoplastic Agents Peptide Plasma protein binding Article Necrosis 03 medical and health sciences Cell Line Tumor Escherichia coli Humans Binding site Receptor lcsh:Science Nuclear Magnetic Resonance Biomolecular Ship2 EphA2 receptor KRI peptide chemistry.chemical_classification Binding Sites Multidisciplinary 030102 biochemistry & molecular biology Drug discovery Receptor EphA2 lcsh:R Membrane Proteins Prostatic Neoplasms Fibroblasts In vitro Sterile Alpha Motif 030104 developmental biology chemistry Biochemistry Drug Design Phosphatidylinositol-3 4 5-Trisphosphate 5-Phosphatases Cancer cell lcsh:Q Peptides Sterile alpha motif Preliminary Data Protein Binding |
| Zdroj: | Scientific Reports, Vol 7, Iss 1, Pp 1-11 (2017) Scientific reports (Nature Publishing Group) 7 (2017). doi:10.1038/s41598-017-17684-5 info:cnr-pdr/source/autori:Mercurio, Flavia Anna; Di Natale, Concetta; Pirone, Luciano; Iannitti, Roberta; Marasco, Daniela; Pedone, Emilia Maria; Palumbo, Rosanna; Leone, Marilisa/titolo:The Sam-Sam interaction between Ship2 and the EphA2 receptor: design and analysis of peptide inhibitors/doi:10.1038%2Fs41598-017-17684-5/rivista:Scientific reports (Nature Publishing Group)/anno:2017/pagina_da:/pagina_a:/intervallo_pagine:/volume:7 Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-017-17684-5 |
| Popis: | The lipid phosphatase Ship2 represents a drug discovery target for the treatment of different diseases, including cancer. Its C-terminal sterile alpha motif domain (Ship2-Sam) associates with the Sam domain from the EphA2 receptor (EphA2-Sam). This interaction is expected to mainly induce pro-oncogenic effects in cells therefore, inhibition of the Ship2-Sam/EphA2-Sam complex may represent an innovative route to discover anti-cancer therapeutics. In the present work, we designed and analyzed several peptide sequences encompassing the interaction interface of EphA2-Sam for Ship2-Sam. Peptide conformational analyses and interaction assays with Ship2-Sam conducted through diverse techniques (CD, NMR, SPR and MST), identified a positively charged penta-amino acid native motif in EphA2-Sam, that once repeated three times in tandem, binds Ship2-Sam. NMR experiments show that the peptide targets the negatively charged binding site of Ship2-Sam for EphA2-Sam. Preliminary in vitro cell-based assays indicate that -at 50 µM concentration- it induces necrosis of PC-3 prostate cancer cells with more cytotoxic effect on cancer cells than on normal dermal fibroblasts. This work represents a pioneering study that opens further opportunities for the development of inhibitors of the Ship2-Sam/EphA2-Sam complex for therapeutic applications. |
| Databáze: | OpenAIRE |
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