The term α-neurotoxin was coined by
C.C. Chang, who designated the postsynaptic
bungarotoxin with the α- prefix because it happened to be slowest moving of the bungarotoxins under starch zone electrophoresis.[3] The "α-" prefix subsequently came to connote any toxins with postsynaptic action. Members of this group are sometimes referred to as "curaremimetics" due to the similarity of their effects with the plant
alkaloidcurare.[4][5]
As more snake venoms were characterized, many were found to contain homologous nAChR-antagonist proteins. These came to be collectively known as the snake venom α-neurotoxins.[5]
General structure
All α-neurotoxins share the
three-finger toxintertiary structure, consisting of a small
globular core containing four
disulfide bonds, three loops or "fingers", and a C-terminal tail.[4]
The class can be divided into two groups distinguished by length; short-chain neurotoxins have 60-62 residues and only the four core disulfide bonds characteristic of the fold, while long-chain neurotoxins have 66 or more residues, often including a longer
C-terminus, and an additional disulfide bond in the second "finger" loop.[4][6] These classes have significant sequence homology and share the same three-dimensional structure, but have differing specificities and kinetics of association/dissociation with the receptor.[7] Localized mobility at the tips of fingers I and II is essential for binding.[8] Accordingly, mutation of these residues produces large effects on binding.[9][6] The additional disulfide bond in the second loop of the long-chain forms is likewise thought to influence binding specificity.[4] Although both short and long-chain neurotoxins bind the same site on their target receptors, short-chain neurotoxins do not potently block α7 homo-oligomeric neuronal AChRs,[10] while long-chain neurotoxins do.[4]α-bungarotoxin and
α-cobratoxin are both long-type.[6]
α-Neurotoxins antagonistically bind tightly and noncovalently to nAChRs of skeletal muscles, thereby blocking the action of ACh at the postsynaptic membrane, inhibiting ion flow and leading to paralysis. nAChRs contain two binding sites for snake venom neurotoxins. Some computational studies of the mechanism of inhibition using
normal mode dynamics[11] suggest that a twist-like motion caused by ACh binding may be responsible for pore opening, and that this motion is inhibited by toxin binding.[11][12]
Evolution
Although three-finger protein domains are widespread, three-finger toxins appear only in snakes, and are particularly enriched in
elapids.[13] There is evidence that alpha-neurotoxins have evolved rapidly and are subject to
positive selection,[14] possibly due to an
evolutionary arms race with prey species.[15]
Snake nAchRs have specific sequence features that render them poor binding partners for alpha-neurotoxins.[16][17] Some
mammalian lineages also display mutations conferring resistance to alpha-neurotoxins; such resistance is believed to have evolved
convergently at least four times in mammals, reflecting two different biochemical mechanisms of adaptation.[18] The introduction of
glycosylation sites on the receptor, resulting in
steric hindrance at the neurotoxin binding site, is a well-characterized resistance mechanism found in
mongooses, while the
honey badger,
domestic pig, and
hedgehog lineages replace
aromatic amino acids with charged residues; at least in some lineages, these molecular adaptations likely reflect
predation on venomous snakes.[18][16]
^
abcdeKini RM, Doley R (November 2010). "Structure, function and evolution of three-finger toxins: mini proteins with multiple targets". Toxicon. 56 (6): 855–67.
doi:
10.1016/j.toxicon.2010.07.010.
PMID20670641.
^Connolly PJ, Stern AS, Hoch JC (January 1996). "Solution structure of LSIII, a long neurotoxin from the venom of Laticauda semifasciata". Biochemistry. 35 (2): 418–26.
doi:
10.1021/bi9520287.
PMID8555211.