The mechanism of cytotoxicity by Naja naja atra cardiotoxin 3 is physically distant from its membrane-damaging effect

Chen, Ku Chung; Kao, Pei Hsiu; Lin, Shinne Ren; Chang, Long

doi:10.1016/j.toxicon.2007.06.011

Cited by 24 publications

(11 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NTs target different muscle and neuronal nicotinic acetylcholine receptors [4]. So far, no specific protein target was revealed for CTs, although its existence has been offered [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Structure and Dynamics of Cardiotoxins

Konshina

Dubovskii²,

Efremov³

2012

CPPS

View full text Add to dashboard Cite

Cytotoxins (or cardiotoxins; CTs) are toxins from cobra venom characterized by the three-finger (TF) fold. CTs are on average 60-residue-long peptides, possessing as many as 4 disulfide bonds. The elements of antiparallel β-structure take origin from the hydrophobic core formed by the disulfides. The β-strands adopt the shape of the three loops, giving the name of the fold. While neurotoxins (NTs) - also TF proteins from snake venom - exert their effect through specific interactions with protein receptors, no specific protein target has been found for CTs. Unlike NTs, CTs are amphiphilic and cytotoxic against a variety of cells, including cancer ones. Thus, the hypothesis that the activity of CTs is caused by their interactions with lipid membranes is currently central. To understand molecular basis behind variations in toxicities of CTs highly homologous in their sequences, detailed knowledge of their structure and dynamics is required. The present review summarizes experimental and computational data on the spatial organization of CTs and their dynamics in various environments (aqueous solution, membranous milieus).

show abstract

“…NTs target different muscle and neuronal nicotinic acetylcholine receptors [4]. So far, no specific protein target was revealed for CTs, although its existence has been offered [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Structure and Dynamics of Cardiotoxins

Konshina

Dubovskii²,

Efremov³

2012

CPPS

View full text Add to dashboard Cite

show abstract

“…Thin-layer chromatography and fluorescence spectroscopy measurements have previously demonstrated that CTs can bind negatively charged lipids and induce membrane leakage by making pores in charged vesicles, whose size and life time have also been estimated [ 6] , [7], [19], [20]. Existence of a specific binding site on the toxin molecule is confirmed by X-ray data [ 17 ].…”

Section: Discussionmentioning

confidence: 83%

“…However, distribution of glycosphingolipids in membranes of various mammalian cell types differs extremely [ 18 ]. Taking into account the extensive profile of CT activity, along with the successful leakage experiments on anionic model membranes lacking sulfatides [ 6] , [19], [20], it is reasonable to propose that CTs may specifically interact with other anionic membrane compounds as well. Here, the term “specifically” indicates binding of one or several lipid molecules (from the bilayer) to the particular sites on the CTs' molecular surface.…”

Section: Introductionmentioning

confidence: 99%

Snake Cytotoxins Bind to Membranes via Interactions with Phosphatidylserine Head Groups of Lipids

et al. 2011

View full text Add to dashboard Cite

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.

show abstract

“…In addition, some other components from NNAV, such as cysteinerich secretory proteins (CRISPs), cardiotoxin (CTX) and neurotoxin (NTX) may also regulate the immune rejection process by modulating expression of cytokines such as ICAM-1, IL-2, IL-10, and E-selectin [9][10][11]. NTX is an alkaline protein purified from NNAV, with a molecular weight about 7 kD [12].…”

Section: Introductionmentioning

confidence: 99%