Molecular characterization of the specificity of interactions of various neurotoxins on two distinct nicotinic acetylcholine receptors.
Snake curaremimetic toxins are currently classified as short-chain and long-chain toxins according to their size and their number of disulfide bonds. All these toxins bind with high affinity to muscular-type nicotinic acetylcholine receptor, whereas only long toxins recognize the alpha7 receptor with high affinity. On the basis of binding experiments with Torpedo or neuronal alpha7 receptors using wild-type and mutated neurotoxins, we characterized the molecular determinants involved in these different recognition processes. The functional sites by which long and short toxins interact with the muscular-type receptor include a common core of highly conserved residues and residues that are specific to each of toxin families. Furthermore, the functional sites through which alpha-cobratoxin, a long-chain toxin, interacts with muscular and alpha7 receptors share similarities but also marked differences. Our results reveal that the three-finger fold toxins have evolved toward various specificities by displaying distinct functional sites.
Servent
D
D
CEA/Saclay, Département d'Ingénierie et d'Etudes des Protéines, 91191 Gif-sur-Yvette, France. denis.servent@cea.fr
Antil-Delbeke
S
S
Gaillard
C
C
Corringer
P J
PJ
Changeux
J P
JP
Ménez
A
A
D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D003039:Cobra Neurotoxin Proteins / Q000235:genetics / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009498:Neurotoxins / Q000235:genetics / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D014101:Torpedo; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; D003039:Cobra Neurotoxin Proteins; D009498:Neurotoxins; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor; C025154:alpha-cobratoxin