Snake inhibitors of phospholipase A2 enzymes

Dunn, Rosanne; Broady, Kevin W.

doi:10.1016/s1388-1981(01)00138-x

Cited by 66 publications

(38 citation statements)

References 47 publications

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“…51 IL-37 IL-37, also known as IL-1F7, is expressed in several tissues and in inflammatory cells. 52 In vitro, induction of IL-37 in macrophages or epithelial cells almost completely suppressed production of proinflammatory cytokines, including IL-1␣, IL-1␤, and TNF␣. 27 Conversely, these proinflammatory cytokines increased with silencing of endogenous IL-37 in human blood cells.…”

Section: Il-33mentioning

confidence: 98%

Recent Advances on the Role of Cytokines in Atherosclerosis

Ait‐Oufella

Taleb

Mallat

et al. 2011

ATVB

502

390

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Section: Il-33mentioning

confidence: 98%

Recent Advances on the Role of Cytokines in Atherosclerosis

Ait‐Oufella

Taleb

Mallat

et al. 2011

ATVB

502

390

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“…a polypeptide chain of ␥-type inhibitors of phospholipases A2 from sera of different snakes contains two repeats with TFT-like fold (35), and urokinase-type plasminogen activator receptor contains three repeats. However, in these proteins the disulfides are only within TFT-like domains but not between them (36).…”

Section: Discussionmentioning

confidence: 99%

Naturally Occurring Disulfide-bound Dimers of Three-fingered Toxins

Osipov

Kasheverov

Makarova

et al. 2008

Journal of Biological Chemistry

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Disulfide-bound dimers of three-fingered toxins have been discovered in the Naja kaouthia cobra venom; that is, the homodimer of ␣-cobratoxin (a long-chain ␣-neurotoxin) and heterodimers formed by ␣-cobratoxin with different cytotoxins. According to circular dichroism measurements, toxins in dimers retain in general their three-fingered folding. The functionally important disulfide 26 -30 in polypeptide loop II of ␣-cobratoxin moiety remains intact in both types of dimers. Biological activity studies showed that cytotoxins within dimers completely lose their cytotoxicity. However, the dimers retain most of the ␣-cobratoxin capacity to compete with ␣-bungarotoxin for binding to Torpedo and ␣7 nicotinic acetylcholine receptors (nAChRs) as well as to Lymnea stagnalis acetylcholine-binding protein. Electrophysiological experiments on neuronal nAChRs expressed in Xenopus oocytes have shown that ␣-cobratoxin dimer not only interacts with ␣7 nAChR but, in contrast to ␣-cobratoxin monomer, also blocks ␣3␤2 nAChR. In the latter activity it resembles -bungarotoxin, a dimer with no disulfides between monomers. These results demonstrate that dimerization is essential for the interaction of three-fingered neurotoxins with heteromeric ␣3␤2 nAChRs. Three-fingered toxins (TFTs)2 are the main components of the Elapidae snake venoms. TFTs consist of one polypeptide chain, their spatial structure being characterized by a hydrophobic core stabilized by four disulfide bridges, which confine three polypeptide loops (fingers). In cobra venom TFTs are represented mainly by ␣-neurotoxins and cytotoxins. So-called short-chain ␣-neurotoxins (60 -62 amino acid residues, 4 intramolecular disulfides) effectively block nicotinic acetylcholine receptors (nAChRs) of muscle-type, and long-chain ␣-neurotoxins (65-75 residues with an additional disulfide in central loop II) block neuronal homopentameric ␣7 nAChR as well (1, 2). These toxins are widely used as tools in the nAChR studies. Cytotoxins, structurally related to short-chain ␣-neurotoxins, manifest another activity; they non-selectively disrupt cell membranes and, thus, kill the cells (3).Another example of TFT interacting with nAChR are -bungarotoxins (-Bgts), minor components of the krait (Elapidae) venom (4, 5). All -Bgts consist of 66 amino acid residues and, similar to long-chain ␣-neurotoxins, contain five disulfide bonds. However, in contrast to ␣-neurotoxins, -Bgts practically do not block muscle-type nAChRs and only weakly act on ␣7 nAChR but with high efficiency interact with ␣3␤2 neuronal receptors (6). Despite the vast array of data on structure-activity relationship for ␣-neurotoxins and -Bgts, it is not yet clear what are the main structural features determining the specificity of a toxin to the particular receptor type. Recently, based on the x-ray structure of ␣-cobratoxin (␣-CT) with acetylcholinebinding protein, Bourne et al. (7) suggested that Lys-29 is the main residue determining the difference in specificity between ␣-neurotoxins and -bungarotoxins. However, A29K mut...

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“…[8][9][10][11][12] Since these venom components are also highly toxic to the snakes themselves when accidentally injected into the bloodstream, venomous snakes possess protective proteins that inhibit venomous enzymes in their blood. For example, several isoforms of PLA 2 inhibitors 13,14) and a habu serum factor (HSF) that inhibits venom MPs 15,16) have been isolated and characterized in the habu. HSF is a 45-kDa glycoprotein whose primary structure shows a common characteristic of fetuin family proteins, and consists of N-terminal repeats of two cystatin-like domains (CY1 and CY2) and a C-terminal histidine-rich domain (HR).…”

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confidence: 99%