Amphiphilic β‐sheet cobra cardiotoxin targets mitochondria and disrupts its network

Wang, Chia-Hui; Wu, Wen‐guey

doi:10.1016/j.febslet.2005.05.006

Cited by 59 publications

(41 citation statements)

References 41 publications

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“…The distinct difference between the lifetimes of CTX A3 pore formation and desensitization we observed in this study and the lifetime of CTX A3 internalization to target mitochondria (27) provides hints to distinguish between the aforementioned mechanisms. In the patch clamp experiment on H9C2 cell membranes (Fig.…”

Section: Discussionmentioning

confidence: 65%

“…Membrane-We have shown previously that CTX A3 targets mitochondria after internalization by H9C2 cells and disrupts the mitochondrial network (27) and that anti-SGC treatment of rat cardiomyocytes can block CTX A3 internalization (25). Fig.…”

Section: Sgc-facilitated Ctx Internalization Occurs After Ctx Pore Fomentioning

confidence: 90%

“…Polyclonal antibodies against CTX were purified from the antivenin of Bungarus multicinctus and N. atra (Center for Disease Control, Taiwan) by immunoprecipitation (27). The specificity of isolated CTX antibodies was verified by immunoblotting.…”

Section: Methodsmentioning

confidence: 99%

“…Fluorescein isothiocyanate (FITC)-CTX A3 was prepared as described previously (25,27), and dipyrromethene boron difluoride (BODIPY)-SGC was provided by Dr. Richard E. Pagano (Mayo Clinic College of Medicine, Rochester, MN). To monitor the internalization of CTX A3, 5 M FITC-CTX A3 was applied to cardiomyocytes or H9C2 cells in the HBSS.…”

Section: Methodsmentioning

confidence: 99%

“…CTXs are also recognized as cytotoxins, with the ability to induce a general lytic effect on human erythrocytes (21), necrotic cell death in fetal rat cardiomyocytes (25), and apoptosis in cortical neurons and human leukemia cells (25,26). The major CTX from Taiwan cobra, CTX A3, targets the mitochondrial membrane after internalization and acts synergistically with a CTX-induced cytosolic calcium increase to disrupt the mitochondrial network (27). Interestingly, by applying the monoclonal antibody O4, which is specific for the 3Ј-sulfated galactose moiety of sulfatides (28), CTX internalization and CTX-induced cytotoxicity of cardiomyocytes can be inhibited efficiently (25).…”

mentioning

confidence: 99%

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Glycosphingolipid-facilitated Membrane Insertion and Internalization of Cobra Cardiotoxin

Wang

Liu

Lee

et al. 2006

Journal of Biological Chemistry

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Cobra cardiotoxins, a family of basic polypeptides having lipidand heparin-binding capacities similar to the cell-penetrating peptides, induce severe tissue necrosis and systolic heart arrest in snakebite victims. Whereas cardiotoxins are specifically retained on the cell surface via heparan sulfate-mediated processes, their lipid binding ability appears to be responsible, at least in part, for cardiotoxin-induced membrane leakage and cell death. Although the exact role of lipids involved in toxin-mediated cytotoxicity remains largely unknown, monoclonal anti-sulfatide antibody O4 has recently been shown to inhibit the action of CTX A3, the major cardiotoxin from Taiwan cobra venom, on cardiomyocytes by preventing cardiotoxin-induced membrane leakage and CTX A3 internalization into mitochondria. Here, we show that anti-sulfatide acts by blocking the binding of CTX A3 to the sulfatides in the plasma membrane to prevent sulfatide-dependent CTX A3 membrane pore formation and internalization. We also describe the crystal structure of a CTX A3-sulfatide complex in a membrane-like environment at 2.3 Å resolution. The unexpected orientation of the sulfatide fatty chains in the structure allows prediction of the mode of toxin insertion into the plasma membrane. CTX A3 recognizes both the headgroup and the ceramide interfacial region of sulfatide to induce a lipid conformational change that may play a key role in CTX A3 oligomerization and cellular internalization. This proposed lipid-mediated toxin translocation mechanism may also shed light on the cellular uptake mechanism of the amphiphilic cell-penetrating peptides known to involve multiple internalization pathways.Glycosphingolipids in eukaryotic cells have important biological functions in membrane trafficking and cell signaling (1, 2). The number of disease-related proteins found to interact specifically with glycosphingolipids is also increasing (3-5). For instance, recent studies have shown that natural killer cells can be activated by glycosylceramides from the cell surface of Gram-negative bacteria that do not contain lipopolysaccharide (6, 7). There is also evidence indicating that, in response to tumor necrosis factor-␣, trafficking of ganglioside GD3 from the plasma membrane to mitochondria can trigger several cell death signaling responses (3,8,9). Although the molecular mechanisms accounting for the observed glycosphingolipid transport and glycolipidtriggered cell responses remain elusive, recent progress in determining the three-dimensional structure of protein⅐glycosphingolipid complexes has shed some light on the process (10 -13). These glycosphingolipid-binding proteins function by either extracting lipids from the membrane and forming a water-soluble protein⅐lipid complex, as in the cases of glycosphingolipid transfer protein, saposin B, and lipid-presenting CD1a (10 -12), or by localizing to a glycosphingolipid domain of the plasma membrane and eventually being internalized via the endocytic pathway, as seen for cholera and Shiga toxins (13,14). Aft...

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Section: Discussionmentioning

confidence: 65%

Section: Sgc-facilitated Ctx Internalization Occurs After Ctx Pore Fomentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Glycosphingolipid-facilitated Membrane Insertion and Internalization of Cobra Cardiotoxin

Wang

Liu

Lee

et al. 2006

Journal of Biological Chemistry

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Privileged frameworks from snake venom

Reeks

Fry

Alewood

2015

Cell. Mol. Life Sci.

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Venom as a form of chemical prey capture is a key innovation that has underpinned the explosive radiation of the advanced snakes (Caenophidia). Small venom proteins are often rich in disulfide bonds thus facilitating stable molecular scaffolds that present key functional residues on the protein surface. New toxin types are initially developed through the venom gland over-expression of normal body proteins, their subsequent gene duplication and diversification that leads to neofunctionalisation as random mutations modify their structure and function. This process has led to preferentially selected (privileged) cysteine-rich scaffolds that enable the snake to build arrays of toxins many of which may lead to therapeutic products and research tools. This review focuses on cysteine-rich small proteins and peptides found in snake venoms spanning natriuretic peptides to phospholipase enzymes, while highlighting their three-dimensional structures and biological functions as well as their potential as therapeutic agents or research tools.

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Latarcins: versatile spider venom peptides

Dubovskii

Vassilevski

Kozlov

et al. 2015

Cell. Mol. Life Sci.

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Arthropod venoms feature the presence of cytolytic peptides believed to act synergetically with neurotoxins to paralyze prey or deter aggressors. Many of them are linear, i.e., lack disulfide bonds. When isolated from the venom, or obtained by other means, these peptides exhibit common properties. They are cationic; being mostly disordered in aqueous solution, assume amphiphilic α-helical structure in contact with lipid membranes; and exhibit general cytotoxicity, including antifungal, antimicrobial, hemolytic, and anticancer activities. To suit the pharmacological needs, the activity spectrum of these peptides should be modified by rational engineering. As an example, we provide a detailed review on latarcins (Ltc), linear cytolytic peptides from Lachesana tarabaevi spider venom. Diverse experimental and computational techniques were used to investigate the spatial structure of Ltc in membrane-mimicking environments and their effects on model lipid bilayers. The antibacterial activity of Ltc was studied against a panel of Gram-negative and Gram-positive bacteria. In addition, the action of Ltc on erythrocytes and cancer cells was investigated in detail with confocal laser scanning microscopy. In the present review, we give a critical account of the progress in the research of Ltc. We explore the relationship between Ltc structure and their biological activity and derive molecular characteristics, which can be used for optimization of other linear peptides. Current applications of Ltc and prospective use of similar membrane-active peptides are outlined.

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Amphiphilic β‐sheet cobra cardiotoxin targets mitochondria and disrupts its network

Cited by 59 publications

References 41 publications

Glycosphingolipid-facilitated Membrane Insertion and Internalization of Cobra Cardiotoxin

Glycosphingolipid-facilitated Membrane Insertion and Internalization of Cobra Cardiotoxin

Privileged frameworks from snake venom

Latarcins: versatile spider venom peptides

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