Molecular Biology and Evolution 18:1800-1809 (2001)
© 2001 Society for Molecular Biology and Evolution
Snake 
-Neurotoxin Binding Site on the Egyptian Cobra (Naja haje) Nicotinic Acetylcholine Receptor Is Conserved
Department of Pharmacology, College of Physicians and Surgeons, Columbia University;
Department of Neurology and Ernest Gallo Clinic and Research Foundation, University of California at San Francisco
Evolutionary success requires that animal venoms are targeted against phylogenetically conserved molecular structures of fundamental physiological processes. Species producing venoms must be resistant to their action. Venoms of Elapidae snakes (e.g., cobras, kraits) contain 
-neurotoxins, represented by -bungarotoxin (-BTX) targeted against the nicotinic acetylcholine receptor (nAChR) of the neuromuscular junction. The model which presumes that cobras (Naja spp., Elapidae) have lost their binding site for conspecific -neurotoxins because of the unique amino acid substitutions in their nAChR polypeptide backbone per se is incompatible with the evolutionary theory that (1) the molecular motifs forming the -neurotoxin target site on the nAChR are fundamental for receptor structure and/or function, and (2) the -neurotoxin target site is conserved among Chordata lineages. To test the hypothesis that the -neurotoxin binding site is conserved in Elapidae snakes and to identify the mechanism of resistance against conspecific -neurotoxins, we cloned the ligand binding domain of the Egyptian cobra (Naja haje) nAChR subunit. When expressed as part of a functional Naja/mouse chimeric nAChR in Xenopus oocytes, this domain confers resistance against -BTX but does not alter responses induced by the natural ligand acetylcholine. Further mutational analysis of the Naja/mouse nAChR demonstrated that an N-glycosylation signal in the ligand binding domain that is unique to N. haje is responsible for -BTX resistance. However, when the N-glycosylation signal is eliminated, the nAChR containing the N. haje sequence is inhibited by -BTX with a potency that is comparable to that in mammals. We conclude that the binding site for conspecific -neurotoxin in Elapidae snakes is conserved in the nAChR ligand binding domain polypeptide backbone per se. This conclusion supports the hypothesis that animal toxins are targeted against evolutionarily conserved molecular motifs. Such conservation also calls for a revision of the present model of the -BTX binding site. The approach described here can be used to identify the mechanism of resistance against conspecific venoms in other species and to characterize toxin-receptor coevolution.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Pawlak, S. P. Mackessy, B. G. Fry, M. Bhatia, G. Mourier, C. Fruchart-Gaillard, D. Servent, R. Menez, E. Stura, A. Menez, et al. Denmotoxin, a Three-finger Toxin from the Colubrid Snake Boiga dendrophila (Mangrove Catsnake) with Bird-specific Activity J. Biol. Chem., September 29, 2006; 281(39): 29030 - 29041. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. S. Rao, S. Swarup, and R. M. Kini The nonenzymatic subunit of pseutarin C, a prothrombin activator from eastern brown snake (Pseudonaja textilis) venom, shows structural similarity to mammalian coagulation factor V Blood, August 15, 2003; 102(4): 1347 - 1354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Hoover, E. Poch, A. Monroy, N. Vazquez, T. Nishio, G. Gamba, and S. C. Hebert N-Glycosylation at Two Sites Critically Alters Thiazide Binding and Activity of the Rat Thiazide-sensitive Na+:Cl- Cotransporter J. Am. Soc. Nephrol., February 1, 2003; 14(2): 271 - 282. [Abstract] [Full Text] [PDF]
|
|