Alpha-neurotoxin

α-Neurotoxins are a group of neurotoxic snake peptides that come from the venom of snakes in the families Elapidae and Hydrophidae that cause paralysis, respiratory failure, and death. They are antagonists of postsynaptic nicotinic acetylcholine receptors (nAChRs) in the neuromuscular synapse that bind competitively and irreversibly, preventing synaptic acetylcholine (ACh) from opening the ion channel. Over 100 α-neurotoxins have been identified and sequenced.

History

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. The "α-" prefix subsequently came to connote any toxins with postsynaptic action.

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.

General Structure

α-Neurotoxins from snake venoms that tightly bind nAChRs contain 60-75 amino acid (aa) residues and are linked by 4-5 disulfide bridges. Of these, there are two kinds, short type and long type, which have significant sequence homology and share the same three-dimensional structure, but have differing kinetics of association/dissociation with the receptor. All α-neurotoxins share a tertiary structure known as the three-finger fold, a four-disulfide globular core from which emerge three loops or fingers and a C-terminal tail. Localized mobility at the tips of fingers I and II is essential for binding. Accordingly, mutation of these residues produces large effects on binding.

Short Type:

Contain four disulfide bridges; composed of 60-62 aa's. Do not potently block α7 homo-oligomeric neuronal AChRs.

Long Type:

Contain a fifth disulfide bridge at the tip of the second loop; composed of 66-75 aa's. Potently block α7 homo-oligomeric neuronal AChRs. α-bungarotoxin and α-cobratoxin are both long-type.

Functions

For specifics, see Alpha-Bungarotoxin and nicotinic acetylcholine receptor

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. Progress towards discovering the dynamics of binding action of these sites has proved difficult, although recent studies using normal mode dynamics have aided in predicting the nature of both the binding mechanisms of snake toxins and of ACh to nAChRs. These studies have shown that a twist-like motion caused by ACh binding is likely responsible for pore opening, and that one or two molecules of α-bungarotoxin (or other long-chain α-neurotoxin) suffice to halt this motion. The toxins seem to lock together neighboring receptor subunits, inhibiting the twist and therefore, the opening motion.