α-Neurotoxins are a group of neurotoxic

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

s found in the

venom Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a sti ...

of snakes in the families

Elapidae Elapidae (, commonly known as elapids , from , variant of "sea-fish") is a family of snakes characterized by their permanently erect fangs at the front of the mouth. Most elapids are venomous, with the exception of the genus '' Emydocephalus ...

and Hydrophiidae. They can cause

paralysis Paralysis (: paralyses; also known as plegia) is a loss of Motor skill, motor function in one or more Skeletal muscle, muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory d ...

respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a r ...

, and death. Members of the

three-finger toxin Three-finger toxins (abbreviated 3FTx) are a protein superfamily of small toxin proteins found in the venom of snakes. Three-finger toxins are in turn members of a larger superfamily of three-finger protein domains which includes non-toxic prote ...

protein family A protein family is a group of evolutionarily related proteins. In many cases, a protein family has a corresponding gene family, in which each gene encodes a corresponding protein with a 1:1 relationship. The term "protein family" should not be ...

, they are

antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the c ...

s (nAChRs) in the neuromuscular

synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

that bind competitively and irreversibly, preventing synaptic

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

(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 Bungarotoxins are toxins found in the venom of snakes and kraits. Bites from these animals can result in severe symptoms including bleeding or hemorrhage, paralysis and tissue damage that can result in amputation. The paralytic effects of venom are ...

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. Members of this group are sometimes referred to as "curaremimetics" due to the similarity of their effects with the plant

alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...

curare Curare ( or ; or ) is a common name for various alkaloid arrow poisons originating from plant extracts. Used as a paralyzing agent by indigenous peoples in Central and South America for hunting and for therapeutic purposes, curare only ...

. 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

All α-neurotoxins share the

tertiary structure Protein tertiary structure is the three-dimensional shape of a protein. The tertiary structure will have a single polypeptide chain "backbone" with one or more protein secondary structures, the protein domains. Amino acid side chains and the ...

, consisting of a small

globular A globular cluster is a spheroidal conglomeration of stars that is bound together by gravity, with a higher concentration of stars towards its center. It can contain anywhere from tens of thousands to many millions of member stars, all orbiting ...

core containing four

disulfide bond In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inor ...

s, three loops or "fingers", and a C-terminal tail. 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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...

, and an additional disulfide bond in the second "finger" loop. 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. Localized mobility at the tips of fingers I and II is essential for binding. Accordingly, mutation of these residues produces large effects on binding. The additional disulfide bond in the second loop of the long-chain forms is likewise thought to influence binding specificity. 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, while long-chain neurotoxins do. α-bungarotoxin and

α-cobratoxin α-Cobratoxin is a substance of the venom of certain ''Naja'' cobras. It is a nicotinic acetylcholine receptor (nAChR) antagonist which causes paralysis by preventing the binding of acetylcholine to the nAChR. Sources α-Cobratoxin is a neuroto ...

are both long-type.

Functions

''For specifics, see α-Bungarotoxin and

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the c ...

'' 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 A normal mode of a dynamical system is a pattern of motion in which all parts of the system move sinusoidally with the same frequency and with a fixed phase relation. The free motion described by the normal modes takes place at fixed frequencies ...

dynamics 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.

Evolution

Although three-finger protein domains are widespread, three-finger toxins appear only in snakes, and are particularly enriched in

elapid Elapidae (, commonly known as elapids , from , variant of "sea-fish") is a family (biology), family of snakes characterized by their permanently erect fangs at the front of the mouth. Most elapids are venomous, with the exception of the genus ...

s. There is evidence that alpha-neurotoxins have evolved rapidly and are subject to

positive selection In population genetics, directional selection is a type of natural selection in which one extreme phenotype is favored over both the other extreme and moderate phenotypes. This genetic selection causes the allele frequency to shift toward the ...

, possibly due to an

evolutionary arms race In evolutionary biology, an evolutionary arms race is an ongoing struggle between competing sets of co-evolving genes, phenotypic and behavioral traits that develop escalating adaptations and counter-adaptations against each other, resembling the ...

with prey species. Snake nAchRs have specific sequence features that render them poor binding partners for alpha-neurotoxins. Some

mammal A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...

ian 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. The introduction of

glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

sites on the receptor, resulting in

steric hindrance Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is generally a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivi ...

at the neurotoxin binding site, is a well-characterized resistance mechanism found in

mongoose A mongoose is a small terrestrial carnivorous mammal belonging to the family Herpestidae. This family has two subfamilies, the Herpestinae and the Mungotinae. The Herpestinae comprises 23 living species that are native to southern Europe, A ...

s, while the

honey badger The honey badger (''Mellivora capensis''), also known as the ratel ( or ), is a mammal widely distributed across Africa, Southwest Asia, and the Indian subcontinent. It is the only living species in both the genus ''Mellivora'' and the subfami ...

domestic pig The pig (''Sus domesticus''), also called swine (: swine) or hog, is an omnivorous, domesticated, even-toed, hoofed mammal. It is named the domestic pig when distinguishing it from other members of the genus '' Sus''. Some authorities cons ...

, and

hedgehog A hedgehog is a spiny mammal of the subfamily Erinaceinae, in the eulipotyphlan family Erinaceidae. There are 17 species of hedgehog in five genera found throughout parts of Europe, Asia, and Africa, and in New Zealand by introduction. The ...

lineages replace

aromatic amino acid An aromatic amino acid is an amino acid that includes an aromaticity, aromatic ring. Among the 20 standard amino acids, histidine, phenylalanine, tryptophan, tyrosine, are classified as aromatic. Properties and function Optical properties Ar ...

s with charged residues; at least in some lineages, these molecular adaptations likely reflect predation on venomous snakes.

References

{{Nicotinic acetylcholine receptor modulators Neurotoxins Nicotinic antagonists Venomous snakes