Resurfacing receptor binding domain of Colicin N to enhance its cytotoxic effect on human lung cancer cells
| Autor: | Chayada Intasuk, Panuwat Lerdvorasap, Natapol Pornputtapong, Jesada Pitchayakorn, Pornchanok Taweecheep, Runglada Jiraratmetacon, Chatchai Chaotham, Wanatchaporn Arunmanee, Methawee Duangkaew, Kanokpol Aphicho, Armini Syamsidi, Pithi Chanvorachote |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Protein resurfacing
Integrin Biophysics medicine.disease_cause Biochemistry Pore forming toxin Structural Biology Colicin Genetics medicine Cytotoxic T cell Inner membrane Escherichia coli ComputingMethodologies_COMPUTERGRAPHICS biology Chemistry Mutagenesis Molecular biology Computer Science Applications Anticancer Apoptosis Cancer cell biology.protein TP248.13-248.65 Research Article Biotechnology |
| Zdroj: | Computational and Structural Biotechnology Journal, Vol 19, Iss, Pp 5225-5234 (2021) Computational and Structural Biotechnology Journal |
| ISSN: | 2001-0370 |
| Popis: | Graphical abstract Colicin N (ColN) is a bacteriocin secreted by Escherichia coli (E. coli) to kill other Gram-negative bacteria by forcefully generating ion channels in the inner membrane. In addition to its bactericidal activity, ColN have been reported to selectively induce apoptosis in human lung cancer cells via the suppression of integrin modulated survival pathway. However, ColN showed mild toxicity against human lung cancer cells which could be improved for further applications. The protein resurfacing strategy was chosen to engineer ColN by extensive mutagenesis at solvent-exposed residues on ColN. The highly accessible Asp and Glu on wildtype ColN (ColNWT) were replaced by Lys to create polycationic ColN (ColN+12). Previous studies have shown that increase of positive charges on proteins leads to the enhancement of mammalian cell penetration as well as increased interaction with negatively charged surface of cancer cells. Those solvent-exposed residues of ColN were identified by Rosetta and AvNAPSA (Average number of Neighboring Atoms Per Sidechain Atom) approaches. The findings revealed that the structural features and stability of ColN+12 determined by circular dichroism were similar to ColNWT. Furthermore, the toxicity of ColN+12 was cancer selective. Human lung cancer cells, H460 and H23, were sensitive to ColN but human dermal papilla cells were not. ColN+12 also showed more potent toxicity than ColNWT in cancer cells. This confirmed that polycationic resurfacing method has enabled us to improve the anticancer activity of ColN towards human lung cancer cells. |
| Databáze: | OpenAIRE |
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