Structure and Dynamics of Cardiotoxins

Abstract

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).

Snake Venom Cytotoxins, Phospholipase A2s, and Zn2+-dependent Metalloproteinases: Mechanisms of Action and Pharmacological Relevance

“…These cytotoxins kill cells by non-selectively disrupting cell membranes [12,14]. Cytotoxins exhibit various physiological effects which are mainly regulated by modifying cell membrane structure and function [2,12,14,28,29]. Various pharmacological applications have been suggested for cytotoxins such as their ability to destroy various types of cancer cells [2,12,14,30].…”

“…The mechanisms for cytotoxin-mediated toxicity include modulating the activity of membrane-bound enzymes, depolarizing excitable membranes of heart cells and of neurons, inhibiting platelet aggregation, inducing hemolysis and cytotoxicity, and bringing about cardiac arrest [12,42,43]. It is widely accepted that most pathological activities of cytotoxins are based on their ability to bind to cell membranes leading to alterations in the organization and function of lipid bilayers [2,10,12,14,29,44]. Snake envenomation due to Naja species is highly prevalent in Africa and mortality is often associated with the potent necrotic activity of Naja -derived cytotoxins.…”

“…Although the precise molecular mechanism of action remains to be elucidated, it is well accepted that basic residues, namely Lys and Arg, are required for the interaction of cytotoxins with negatively charged phospholipids that are located on the outer leaflets of lipid bilayers [51] (Figure 1). While α-neurotoxins (also TF proteins from cobra venom) mainly exert their pathological effects by physically interacting with select protein receptors, no specific protein targets have yet been identified for cytotoxins from cobra venom [29]. …”

Latarcins: versatile spider venom peptides

“…The latter are polycationic disulfide-rich membraneactive proteins from snake venom, carrying a positive charge, similar to that of Ltc [109,110]. Due to structural rigidity of CT and availability of extensive data on their interaction with model phospholipid membranes, it became possible to specify molecular factors important either for destabilization of the plasma membrane or penetration through the outer envelope of bacteria [108].…”

Peptide and Protein Neurotoxin Toolbox in Research on Nicotinic Acetylcholine Receptors

“…One of the most well-represented groups in the snake venoms are so-called cytotoxins (some of them were earlier called cardiotoxins) which apparently do not have a single well-defined target but disrupt the cell membranes thus inducing a multitude of effects (see reviews [51,52]). As a result of proteomic studies new three-finger proteins are being found in the snake venoms, and one of the minor components in the Naja kaouthia cobra venom was identified as a glycosylated cytotoxin I [53].…”