Structure and pharmacology of elapid cytotoxins

Dufton, Mark J.; Hider, Robert C.

doi:10.1016/0163-7258(88)90111-8

Cited by 172 publications

(145 citation statements)

References 109 publications

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“…However, similar to the lactosylceramide that binds to glycosphingolipid transfer protein or the SGC self-antigen in complex with CD1a, the specificity of the CTX A3-SGC interaction is achieved through recognition and anchoring of both the headgroup and the ceramide interfacial region. The galactose moiety of the bound SGC forms extensive hydrogen bonds with the side chain nitrogens of Lys 12 and Lys 18 and the backbone oxygens of Arg 36 and Cys 38 of CTX A3 monomer A. The side chain of Lys 44 is the only residue in CTX A3 monomer B that lies above the galactose moiety and interacts with the amide region of the ceramide moiety (Fig.…”

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

confidence: 99%

“…10C, the sphingosine alkyl chain of SGC protrudes into the detergent-rich solvent area, and the fatty acid alkyl chain inserts into a symmetry-related D1 dimer. This buried hydrophobic tail adopts a curved, U-shaped conformation and makes van der Waals contacts with the L3 region containing Asp 40 -Lys 44 of monomer AЈ as well as regions including Pro 15 -Lys 18 and Ile 39 -Asp 40 of monomer BЈ. Barring the involvement of side chain reorientations near the tip of the loops in mediating the dimerization of CTX A3, the overall structure of CTX A3 remains unchanged after CTX-membrane interaction due to the presence of four disulfide bonds.…”

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

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: Sgc-facilitated Ctx Internalization Occurs After Ctx Pore Fomentioning

confidence: 99%

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

confidence: 99%

Glycosphingolipid-facilitated Membrane Insertion and Internalization of Cobra Cardiotoxin

Wang

Liu

Lee

et al. 2006

Journal of Biological Chemistry

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“…CTX has also been named cytotoxin because it brings about membrane leakage against many cells including red blood cells and phospholipid membrane vesicles (2). This effect is due in part to the interaction of CTX with phospholipid bilayer.…”

mentioning

confidence: 99%

“…For instance, local conformational changes in L1 (Val-7-Pro-8 peptide bond) of cytotoxin II from Naja oxiana strongly reduce the binding of its minor (with cis-Pro-8) form as compared with the major (with trans-Pro-8) one to membranes (8,12). CTX A3, a major component (Ͼ50% dried weight of all CTXs) of the venom of Taiwan cobra (2,4), is a 60-residue P-type CTX (Fig. 1A).…”

mentioning

confidence: 99%

Structural Basis of Membrane-induced Cardiotoxin A3 Oligomerization

Forouhar

Huang

Liu

et al. 2003

Journal of Biological Chemistry

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Cobra cardiotoxins (CTXs) have previously been shown to induce membrane fusion of vesicles formed by phospholipids such as cardiolipin or sphingomyelin. CTX can also form a pore in membrane bilayers containing a anionic lipid such as phosphatidylserine or phosphatidylglycerol. Herein, we show that the interaction of CTX with negatively charged lipids causes CTX dimerization, an important intermediate for the eventual oligomerization of CTX during the CTX-induced fusion and pore formation process. The structural basis of the lipid-induced oligomerization of CTX A3, a major CTX from Naja atra, is then illustrated by the crystal structure of CTX A3 in complex with SDS; SDS likely mimics anionic lipids of the membrane under micelle conditions at 1.9-Å resolution. The crystal packing reveals distinct SDS-free and SDS-rich regions; in the latter two types of interconnecting CTX A3 dimers, D1 and D2, and several SDS molecules can be identified to stabilize D1 and D2 by simultaneously interacting with residues at each dimer interface. When the three CTX-SDS complexes in the asymmetric unit are overlaid, the orientation of CTX A3 monomers relative to the SDS molecules in the crystal is strikingly similar to that of the toxin with respect to model membranes as determined by NMR and Fourier transform infrared methods. These results not only illustrate how lipid-induced CTX dimer formation may be transformed into oligomers either as inverted micelles of fusion intermediates or as membrane pore of anionic lipid bilayers but also underscore a potential role for SDS in x-ray diffraction study of protein-membrane interactions in the future.

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“…Very little is known about the mechanism of action of the snake venom cardiotoxins (Dufton & Hider, 1988), so the significance, if any, of their structural resemblance to CD59 remains unknown. In the light of the structural similarity of CD59 and WGA, it is intriguing that WGA causes proliferation of human T cells in vitro (Brown et al, 1976), as does CD59 (Deckert et al, 1992).…”

Section: Comparison Of Cd59 With Other Proteinsmentioning

confidence: 99%

Sequence‐specific

Fletcher¹,

Harrison²,

Lachmann³

et al. 1993

Protein Science

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CD59 is a recently discovered cell-surface glycoprotein that restricts lysis by homologous complement and has limited sequence similarity to snake venom neurotoxins. This paper describes the first results of a two-dimensional NMR study of CD59 prepared from human urine. Nearly complete 'H-NMR assignments were obtained for the 77 amino acid residues and partial assignments for the N-glycan and the glycosylphosphatidylinositol (GPI) anchor. These results together confirm that the C-terminal residue of the mature protein is Asn 77 and that the urine-derived form retains the nonlipid part of the GPI anchor. The data further indicate that the GPI anchor and possibly the N-glycan are structurally inhomogeneous and suggest that the phospholipid present in the intact GPI anchor was removed by phosphatidylinositol-specific phospholipase-D. The folding topology of the protein was determined from NOE enhancements and slowly exchanging backbone amide protons and consists primarily of five extended strands (denoted p l -f l 5 in sequence order), arranged into separate two-stranded (PI and &) and three-stranded (&&) antiparallel P-sheets. The same folding topology is found in all of the snake venom neurotoxins whose structures have been determined. The region between the & and & strands has helical character, a feature that is not present in the neurotoxins but that is seen in the topologically similar wheat germ agglutinin.

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Structure and pharmacology of elapid cytotoxins

Cited by 172 publications

References 109 publications

Glycosphingolipid-facilitated Membrane Insertion and Internalization of Cobra Cardiotoxin

Glycosphingolipid-facilitated Membrane Insertion and Internalization of Cobra Cardiotoxin

Structural Basis of Membrane-induced Cardiotoxin A3 Oligomerization

Sequence‐specific

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