Snake cytotoxins bind to membranes via interactions with phosphatidylserine head groups of lipids.

The major representatives of Elapidae snake venom, cytotoxins (CTs), share similar three-fingered fold and exert diverse range of biological activities against various cell types. CT-induced cell death starts from the membrane recognition process, whose molecular details remain unclear. It is known,...

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Autores principales:	Anastasia G Konshina, Ivan A Boldyrev, Yuri N Utkin, Anton V Omel'kov, Roman G Efremov
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/249c7ce147f6491483a142390f4c6255
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spelling	oai:doaj.org-article:249c7ce147f6491483a142390f4c62552021-11-18T06:54:39ZSnake cytotoxins bind to membranes via interactions with phosphatidylserine head groups of lipids.1932-620310.1371/journal.pone.0019064https://doaj.org/article/249c7ce147f6491483a142390f4c62552011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21559494/?tool=EBIhttps://doaj.org/toc/1932-6203The major representatives of Elapidae snake venom, cytotoxins (CTs), share similar three-fingered fold and exert diverse range of biological activities against various cell types. CT-induced cell death starts from the membrane recognition process, whose molecular details remain unclear. It is known, however, that the presence of anionic lipids in cell membranes is one of the important factors determining CT-membrane binding. In this work, we therefore investigated specific interactions between one of the most abundant of such lipids, phosphatidylserine (PS), and CT 4 of Naja kaouthia using a combined, experimental and modeling, approach. It was shown that incorporation of PS into zwitterionic liposomes greatly increased the membrane-damaging activity of CT 4 measured by the release of the liposome-entrapped calcein fluorescent dye. The CT-induced leakage rate depends on the PS concentration with a maximum at approximately 20% PS. Interestingly, the effects observed for PS were much more pronounced than those measured for another anionic lipid, sulfatide. To delineate the potential PS binding sites on CT 4 and estimate their relative affinities, a series of computer simulations was performed for the systems containing the head group of PS and different spatial models of CT 4 in aqueous solution and in an implicit membrane. This was done using an original hybrid computational protocol implementing docking, Monte Carlo and molecular dynamics simulations. As a result, at least three putative PS-binding sites with different affinities to PS molecule were delineated. Being located in different parts of the CT molecule, these anion-binding sites can potentially facilitate and modulate the multi-step process of the toxin insertion into lipid bilayers. This feature together with the diverse binding affinities of the sites to a wide variety of anionic targets on the membrane surface appears to be functionally meaningful and may adjust CT action against different types of cells.Anastasia G KonshinaIvan A BoldyrevYuri N UtkinAnton V Omel'kovRoman G EfremovPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 4, p e19064 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anastasia G Konshina Ivan A Boldyrev Yuri N Utkin Anton V Omel'kov Roman G Efremov Snake cytotoxins bind to membranes via interactions with phosphatidylserine head groups of lipids.
description	The major representatives of Elapidae snake venom, cytotoxins (CTs), share similar three-fingered fold and exert diverse range of biological activities against various cell types. CT-induced cell death starts from the membrane recognition process, whose molecular details remain unclear. It is known, however, that the presence of anionic lipids in cell membranes is one of the important factors determining CT-membrane binding. In this work, we therefore investigated specific interactions between one of the most abundant of such lipids, phosphatidylserine (PS), and CT 4 of Naja kaouthia using a combined, experimental and modeling, approach. It was shown that incorporation of PS into zwitterionic liposomes greatly increased the membrane-damaging activity of CT 4 measured by the release of the liposome-entrapped calcein fluorescent dye. The CT-induced leakage rate depends on the PS concentration with a maximum at approximately 20% PS. Interestingly, the effects observed for PS were much more pronounced than those measured for another anionic lipid, sulfatide. To delineate the potential PS binding sites on CT 4 and estimate their relative affinities, a series of computer simulations was performed for the systems containing the head group of PS and different spatial models of CT 4 in aqueous solution and in an implicit membrane. This was done using an original hybrid computational protocol implementing docking, Monte Carlo and molecular dynamics simulations. As a result, at least three putative PS-binding sites with different affinities to PS molecule were delineated. Being located in different parts of the CT molecule, these anion-binding sites can potentially facilitate and modulate the multi-step process of the toxin insertion into lipid bilayers. This feature together with the diverse binding affinities of the sites to a wide variety of anionic targets on the membrane surface appears to be functionally meaningful and may adjust CT action against different types of cells.
format	article
author	Anastasia G Konshina Ivan A Boldyrev Yuri N Utkin Anton V Omel'kov Roman G Efremov
author_facet	Anastasia G Konshina Ivan A Boldyrev Yuri N Utkin Anton V Omel'kov Roman G Efremov
author_sort	Anastasia G Konshina
title	Snake cytotoxins bind to membranes via interactions with phosphatidylserine head groups of lipids.
title_short	Snake cytotoxins bind to membranes via interactions with phosphatidylserine head groups of lipids.
title_full	Snake cytotoxins bind to membranes via interactions with phosphatidylserine head groups of lipids.
title_fullStr	Snake cytotoxins bind to membranes via interactions with phosphatidylserine head groups of lipids.
title_full_unstemmed	Snake cytotoxins bind to membranes via interactions with phosphatidylserine head groups of lipids.
title_sort	snake cytotoxins bind to membranes via interactions with phosphatidylserine head groups of lipids.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/249c7ce147f6491483a142390f4c6255
work_keys_str_mv	AT anastasiagkonshina snakecytotoxinsbindtomembranesviainteractionswithphosphatidylserineheadgroupsoflipids AT ivanaboldyrev snakecytotoxinsbindtomembranesviainteractionswithphosphatidylserineheadgroupsoflipids AT yurinutkin snakecytotoxinsbindtomembranesviainteractionswithphosphatidylserineheadgroupsoflipids AT antonvomelkov snakecytotoxinsbindtomembranesviainteractionswithphosphatidylserineheadgroupsoflipids AT romangefremov snakecytotoxinsbindtomembranesviainteractionswithphosphatidylserineheadgroupsoflipids
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Snake cytotoxins bind to membranes via interactions with phosphatidylserine head groups of lipids.

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