Three-dimensional structures of neurotoxins and cardiotoxins

Rees, B.; Bilwes, A.M.

doi:10.1021/tx00034a001

Cited by 64 publications

(43 citation statements)

References 135 publications

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“…This fact accords well with the similarity of the folding motif for two families of toxins and strong differences in their functioning. There is also a good correlation with experimentally observed participation of residues 25, 27, 29, 31, 33, 37, 38, 42 and 53 of neurotoxins in binding with acetylcholine receptor ( [1,29], see also references in [15]), and involvement of residues 15, 21, 25 and 43 in cardiotoxin's functioning ( [30] and references therein). Recent NMR experiments also suggest the interaction of the side chains of hydrophobic residues of toxin y in the segments 5-14, 25-35, 39~,6 and 54-58 with the detergent micelles [31].…”

Section: Resultssupporting

confidence: 71%

“…Neurotoxins bind to the nicotinic acetylcholine receptor with very high affinities and block postsynaptic neurotransmission. Cardiotoxins exert a variety of actions on different cells causing cytotoxicity, depolarization of membranes of excitable cells, muscle contraction and hemolysis, suggesting that these toxins act by perturbing of cell membranes (see review [15]). Still the mode of action of cardiotoxins is poorly understood at the molecular level.…”

Section: Introductionmentioning

confidence: 99%

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Amino acid residue: is it structural or functional?

et al. 1995

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A new approach is suggested for delineating the structural and functional amino acid residues in proteins with known three-dimensional structure, basing on the involvement of residues in intramolecular hydrophobic and hydrophilic interactions and additional information about the conservativity of the residues. The approach is applied to the families of homologous neurotoxins and cardiotoxins. The results obtained concerning the role of amino acid residues in both families of toxins accord well with the similarity of their fold, but different mechanisms of action. Current approach can be used for detailed characterization of protein spatial structures, as well as for rational protein engineering.

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Section: Resultssupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Amino acid residue: is it structural or functional?

et al. 1995

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“…The sequence C C X X X X C N was chosen as (a) the asparagine is the only invariant non-cysteine residue in the uPAR/Ly-6 consensus, and (b) the motif forms a short loop structure as its second and third cysteines are disulphide bonded. The search identified the large family of snake venom ~-neurotoxins, exemplified by the acetylcholine receptor antagonist c~-bungarotoxin [31][32][33]. These secreted proteins are of similar size to the uPAR/Ly-6 domains, and most importantly have eight cysteine residues that are comparably spaced and identically paired to those of uPAR (Fig.…”

Section: Similarity To Snake Venom ~-Neurotoxins -A Possible Templatementioning

confidence: 99%

Structure—function relationships in the receptor for urokinase‐type plasminogen activator Comparison to other members of the Ly‐6 family and snake venom α‐neurotoxins

1994

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Plasminogen activation is regulated by the interaction between urokinase-type plasminogen activator (UPA) and its specific glycolipid-anchored cell surface receptor (uPAR). uPAR is composed of three homologous domains and is the only multi-domain member of the Ly-6 family of glycolipid-anchored membrane proteins. Recent evidence has highlighted similarities between the individual domains of uPAR and the large family of secreted, single domain snake venom a-neurotoxins, suggesting that uPAR may adopt the same gross folding pattern as these structurally well characterized proteins. Structural aspects of the binding between ol-neurotoxins and the acetylcholine receptor may have a major influence on future studies of the interaction between uPA and uPAR.

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“…In addition, we recently solved the crystal structure of the ActRII ECD (20) expressed and purified from yeast (21). The ActRII ECD consists of seven disulfide-cross-linked ␤ sheets that form a three-finger toxinlike fold similar to the folds of several cobra cardiotoxins (22). By solving the ECD crystal structure, we were able to identify surface-exposed amino acid residues that may play an important role in protein-protein interactions such as receptor-ligand or receptor-receptor binding interactions (20).…”

mentioning

confidence: 99%

Identification of a Binding Site on the Type II Activin Receptor for Activin and Inhibin

Gray¹,

Greenwald²,

Blount³

et al. 2000

Journal of Biological Chemistry

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Type II activin receptors (ActRII and ActRIIB) are single-transmembrane domain serine/threonine kinase receptors that bind activin to initiate the signaling and cellular responses triggered by this hormone. Inhibin also binds type II activin receptors and antagonizes many activin effects. Here we describe alanine scanning mutagenesis of the ActRII extracellular domain. We identify a cluster of three hydrophobic residues (Phe 42 , Trp 60 , and Phe 83 ) that, when individually mutated to alanine in the context of the full-length receptor, cause the disruption of activin and inhibin binding to ActRII. Each of the alanine-substituted ActRII mutants retaining activin binding maintains the ability to form crosslinked complexes with activin and supports activin cross-linking to the type I activin receptor ALK4. Unlike wild-type ActRII, the three mutants unable to bind activin do not cause an increase in activin signaling when transiently expressed in a corticotroph cell line. Together, our results implicate these residues in forming a critical binding surface on ActRII required for functional interactions with both activin and inhibin. This first identification of a transforming growth factor-␤ family member binding site may provide a general basis for characterizing binding sites for other members of the superfamily.Activins and inhibins (1) belong to the transforming growth factor-␤ (TGF-␤) 1 family of growth and differentiation factors (2) and were originally identified based on their role in regulating reproductive function. Activin was first identified and isolated based on its ability to stimulate the release of folliclestimulating hormone from gonadotrophs in the anterior pituitary (3), whereas inhibin was identified based on its ability to inhibit this process (4). Activins (ϳ28,000 Da) and inhibins (ϳ32,000 Da) are disulfide-linked dimers of related polypeptides, with activins consisting of two ␤ chains (activin A, ␤A-␤A; activin AB, ␤A-␤B; and activin B, ␤B-␤B) and inhibins possessing an ␣ chain disulfide-linked to a ␤ chain (inhibin A, ␣-␤A; and inhibin B, ␣-␤B) (1). The structure of these factors is determined by several conserved cysteine residues that form disulfide bonds in the tightly folded "cystine-knot" motif shared by TGF-␤ superfamily members (6). Although inhibins frequently counteract the effects of activins (7), there are cell types in which inhibin is unable to attenuate the activin response (8, 9), making it unlikely that inhibin blocks activin effects exclusively by competing with activin for receptor binding as has been previously suggested (10).Type II activin receptors (ActRII and the closely related ActRIIB) are single-transmembrane domain serine/threonine kinase receptors that bind activin with high affinity and thereby initiate the cellular responses triggered by activin (11)(12)(13)(14). Like TGF-␤ receptors (15), activin receptors are thought to exist as homodimers, a finding consistent with their proposed role in binding dimeric ligand. Inhibin also binds ActRII and ActRIIB, although...

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Three-dimensional structures of neurotoxins and cardiotoxins

Cited by 64 publications

References 135 publications

Amino acid residue: is it structural or functional?

Amino acid residue: is it structural or functional?

Structure—function relationships in the receptor for urokinase‐type plasminogen activator Comparison to other members of the Ly‐6 family and snake venom α‐neurotoxins

Identification of a Binding Site on the Type II Activin Receptor for Activin and Inhibin

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