Three-finger protein

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Erabutoxin A, a neurotoxin that is a member of the three-finger toxin superfamily. The three "fingers" are labeled I, II, and III, and the four conserved disulfide bonds are shown in yellow. Rendered from PDB: 1QKD . 1qkd 3ftx.png
Erabutoxin A, a neurotoxin that is a member of the three-finger toxin superfamily. The three "fingers" are labeled I, II, and III, and the four conserved disulfide bonds are shown in yellow. Rendered from PDB: 1QKD .
Three-finger protein
CATH 1qkd

Three-finger proteins or three-finger protein domains (3FP or TFPD) are a protein superfamily consisting of small, roughly 60-80 amino acid residue protein domains with a common tertiary structure: three beta strand loops extended from a hydrophobic core stabilized by disulfide bonds. The family is named for the outstretched "fingers" of the three loops. Members of the family have no enzymatic activity, but are capable of forming protein-protein interactions with high specificity and affinity. The founding members of the family, also the best characterized by structure, are the three-finger toxins found in snake venom, which have a variety of pharmacological effects, most typically by disruption of cholinergic signaling. The family is also represented in non-toxic proteins, which have a wide taxonomic distribution; 3FP domains occur in the extracellular domains of some cell-surface receptors as well as in GPI-anchored and secreted globular proteins, usually involved in signaling. [2] [3] [4] [5]


Three-finger toxins

The founding members of the 3FP family are the three-finger toxins (3FTx) often found in snake venom. 3FTx proteins are widely distributed in venomous snake families, but are particularly enriched in the family Elapidae, in which the relative proportion of 3FTx to other venom toxins can reach 95%. [4] [6] Many 3FTx proteins are neurotoxins, though the mechanism of toxicity varies significantly even among proteins of relatively high sequence identity; common protein targets include those involved in cholinergic signaling, such as the nicotinic acetylcholine receptors, muscarinic acetylcholine receptors, and acetylcholinesterase. Another large subfamily of 3FTx proteins is the cardiotoxins (also known as cytotoxins or cytolysins); this group is directly cytotoxic most likely due to interactions with phospholipids and possibly other components of the cell membrane. [2]

Ly6/uPAR family

The human CD59 protein, which regulates the complement system. CD59 2j8b.png
The human CD59 protein, which regulates the complement system.

The Ly6/uPAR family broadly describes a gene family containing three-finger protein domains that are not toxic and not venom components; these are often known as LU domains and can be found in the extracellular domains of cell-surface receptors and in either GPI-anchored or secreted globular proteins. [4] [8] The family is named for two representative groups of members, the small globular protein lymphocyte antigen 6 (LY6) family and the urokinase plasminogen activator receptor (uPAR). [9] Other receptors with LU domains include members of the transforming growth factor beta receptor (TGF-beta) superfamily, such as the activin type 2 receptor; [10] and bone morphogenetic protein receptor, type IA. [11] Other LU domain proteins are small globular proteins such as CD59 antigen, LYNX1, SLURP1, and SLURP2. [4] [12]

Many LU domain containing proteins are involved in cholinergic signaling and bind acetylcholine receptors, notably linking their function to a common mechanism of 3FTx toxicity. [4] [8] [13] Members of the Ly6/uPAR family are believed to be the evolutionary ancestors of 3FTx toxins. [14] Other LU proteins, such as the CD59 antigen, have well-studied functions in regulation of the immune system. [13]

Gene structure

Snake three-finger toxins and the Ly6/uPAR family members share a common gene structure, typically consisting of two introns and three exons. The sequence of the first exon is generally well conserved compared to the other two. [4] The third exon contains the major differentiating features between the two groups, as this is where the C-terminal GPI-anchor peptide common among the Ly6/uPAR globular proteins is encoded. [4] [13]

Evolution and taxonomic distribution

Proteins of the general three-finger fold are widely distributed among metazoans. [4] A 2008 bioinformatics study identified about 45 examples of such proteins, containing up to three three-finger domains, represented in the human genome. [12] A more recent profile of the Ly6/uPAR gene family identified 35 human and at least 61 mouse family members in the organisms' respective genomes. [8]

The three-finger protein family is thought to have expanded through gene duplication in the snake lineage. [14] [15] 3FTx toxins are considered restricted to the Caenophidia, the taxon containing all venomous snakes; however at least one homolog has been identified in the Burmese python, a closely related subgroup. [16] Traditionally, 3FTx genes have been thought to have evolved by repeated events of duplication followed by neofunctionalization and recruitment to gene expression patterns restricted to venom glands. [14] [15] However, it has been argued that this process should be extremely rare and that subfunctionalization better explains the observed distribution. [17] More recently, non-toxic 3FP proteins have been found to be widely expressed in many different tissues in snakes, prompting the alternative hypothesis that proteins of restricted expression in saliva were selectively recruited for toxic functionality. [16]

Related Research Articles

Venom Form of toxin secreted by an animal for the purpose of causing harm to another

Venom is a secretion containing one or more toxins produced by an animal. Venom has evolved in a wide variety of animals, both predators and prey, and both vertebrates and invertebrates.

Snake venom Highly modified saliva containing zootoxins

Snake venom is a highly modified saliva containing zootoxins that facilitate the immobilization and digestion of prey, and defense against threats. It is injected by unique fangs during a bite, and some species are also able to spit their venom.

A latrotoxin is a high-molecular mass neurotoxin found in the venom of spiders of the genus Latrodectus. Latrotoxins are the main active components of the venom and are responsible for the symptoms of latrodectism.

Alpha-Bungarotoxin chemical compound

α-Bungarotoxin (α-BTX) is one of the bungarotoxins, components of the venom of the elapid Taiwanese banded krait snake. It is a type of α-neurotoxin, a neurotoxic protein that is known to bind competitively and in a relatively irreversible manner to the nicotinic acetylcholine receptor found at the neuromuscular junction, causing paralysis, respiratory failure, and death in the victim. It has also been shown to play an antagonistic role in the binding of the α7 nicotinic acetylcholine receptor in the brain, and as such has numerous applications in neuroscience research.


Calciseptine (CaS) is a natural neurotoxin isolated from the black mamba Dendroaspis p. polylepis venom. This toxin consists of 60 amino acids with four disulfide bonds. Calciseptine specifically blocks L-type calcium channels, but not other voltage-dependent Ca2+ channels such as N-type and T-type channels.

Taipoxin is a potent myo- and neurotoxin, which was isolated from the venom of the coastal taipan Oxyuranus scutellatus or also known as the common taipan. Taipoxin like many other pre-synaptic neurotoxins are phospholipase A2 (PLA2) toxins, which inhibit/complete block the release of the motor transmitter acetylcholine and lead to death by paralysis of the respiratory muscles (asphyxia). It is the most lethal neurotoxin isolated from any snake venom to date.

Cobratoxin chemical compound

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.

Choline transporter protein-coding gene in the species Homo sapiens

The high-affinity choline transporter (ChT) also known as solute carrier family 5 member 7 is a protein in humans that is encoded by the SLC5A7 gene. It is a cell membrane transporter and carries choline into acetylcholine-synthesizing neurons.

LU domain InterPro Domain

The LU domain is an evolutionally conserved protein domain of the three-finger protein superfamily. This domain is found in the extracellular domains of cell-surface receptors and in either GPI-anchored or secreted globular proteins, for example the Ly-6 family, CD59, and Sgp-2.


α-Neurotoxins are a group of neurotoxic peptides found in the venom of snakes in the families Elapidae and Hydrophiidae. They can cause paralysis, respiratory failure, and death. Members of the three-finger toxin protein family, they are antagonists of post-synaptic 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.


Mambalgins are peptides found in the venom of the black mamba, an elapid snake. Mambalgins are members of the three-finger toxin (3FTx) protein family and have the characteristic three-finger protein fold. First reported by French researchers in 2012, mambalgins are unusual members of the 3FTx family in that they have the in vivo effect of causing analgesia without apparent toxicity. Their mechanism of action is potent inhibition of acid-sensing ion channels.

Muscarinic toxin 1

Muscarinic toxin 1 (MT1) belongs to the family of small peptides of 65 amino acid residues derived from the venom of African mamba snakes, with dual specificity for muscarinic receptor subtypes M1 and M4. Muscarinic toxins like the nicotinic toxins have the three-finger fold structure, characteristic of the large superfamily of toxins that act at cholinergic synapses.

Evolution of snake venom The origin and diversification of snake venom through geologic time

Venom in snakes and some lizards is a form of saliva that has been modified into venom over its evolutionary history. In snakes, venom has evolved to kill or subdue prey, as well as to perform other diet-related functions. The evolution of venom is thought to be responsible for the enormous expansion of snakes across the globe.


Kappa-bungarotoxin is a protein neurotoxin of the bungarotoxin family that is found in the venom of the many-banded krait, a snake found in Taiwan. Kappa-bungarotoxin is a high affinity antagonist of nicotinic acetylcholine receptors (nAChRs), particularly of CHRNA3; it causes a post-synaptic blockade of neurotransmission. Although there is significant variability in the clinical effects of snake bites, neuromuscular paralysis and respiratory failure are associated with krait bites.

Three-finger toxin InterPro Domain

Three-finger toxins 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 proteins that share a similar protein fold. The group is named for its common structure consisting of three beta strand loops connected to a central core containing four conserved disulfide bonds. The 3FP protein domain has no enzymatic activity and is typically between 60-74 amino acid residues long. Despite their conserved structure, three-finger toxin proteins have a wide range of pharmacological effects. Most members of the family are neurotoxins that act on cholinergic intercellular signaling; the alpha-neurotoxin family interacts with muscle nicotinic acetylcholine receptors (nAChRs), the kappa-bungarotoxin family with neuronal nAChRs, and muscarinic toxins with muscarinic acetylcholine receptors (mAChRs).


Irditoxin is a three-finger toxin (3FTx) protein found in the venom of the brown tree snake and likely in other members of the genus Boiga. It is a heterodimer composed of two distinct protein chains, each of the three-finger protein fold, linked by an intermolecular disulfide bond. This structure is unusual for 3FTx proteins, which are most commonly monomeric.

Mipartoxin-I is a neurotoxin produced by Micrurus mipartitus, a venomous coral snake distributed in Central and South America. This toxin causes a neuromuscular blockade by blocking the nicotinic acetylcholine receptor. It is the most abundant component in the venom.

Long neurotoxin 1 (LNTX-1) is a neurotoxin that binds antagonistically to all types of muscular and neuronal nicotinic acetylcholine receptors. LNTX-1 is found in the venom of the king cobra.

Crotoxin (CTX) is the main toxic compound in the snake venom of the South American rattlesnake, Crotalus durissus terrificus. Crotoxin is a heterodimeric beta-neurotoxin, composed of an acidic, non-toxic and non-enzymatic subunit (CA), and a basic, weakly toxic, phospholipase A2 protein (CB). This neurotoxin causes paralysis by both pre- and postsynaptic blocking of acetylcholine signalling.

LYPD6B protein-coding gene in the species Homo sapiens

LY6/PLAUR Domain Containing 6B, also known under the name Cancer/Testis Antigen 116 (CTA116) and LYPD7 is encoded by the LYPD6B gene. LYPD6B is a member of the lymphocyte antigen 6 (LY6) protein family. It is expressed in the testis, lungs, stomach and the prostate and in the nervous system where it acts as a modulator of nicotinic acetylcholine receptor activity.


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