Snake three-finger toxin family

General
Three-finger toxins (3FTs) are non-enzymatic peptides found in all families of snakes. They are characterized by specific folding of three beta-sheet loops (“fingers”) extending from the central core and by four conserved disulfide bridges. The three loops that project from the core region resemble three outstretched fingers of the hand and hence the name.

Despite their structural similarity, they differ widely in their targets that are numerous: L-type calcium channels (see entries ), sodium channels (see entries ), integrin receptors (see entries ), cell membrane phospholipids (see entries ), acetylcholinesterase (see entries ), nicotinic acetylcholine (see entries ) or muscarinic, adrenergic and dopaminergic receptors (see entries ).

3D-structure view (PDB 1IJC ) of the three-finger toxin bucandin.

Classification
The 3FT family is classified in three categories (long, short and non-conventional), depending on the number and position of disulfide bonds.

long-chain
short-chain
non-conventional

Figure 1: Alignment of long, short and non-conventional 3FTs, with the common disulfide pairing (full lines) and the 5th disulfide pairing of long-chain and non-conventional subfamilies (dashed lines). κ-bgt (κ-1-bungarotoxin ), α-EPTX-Ls2a (α-elapitoxin-Ls2a ), γ-bgt (γ-bungarotoxin ), WTX (Weak tryptophan-containing neurotoxin ), CTX-1 (Cytotoxin 1 ) and CBT (Cobrotoxin ).




The long-chain subfamily
This subfamily contains long 3FTs (66-79 amino acid residues) with a 5th disulfide bond in the second loop and, in most cases, a C-terminal extension (Fig.1). It is subdivided in two sub-subfamilies:

• Kappa-neurotoxin
• Type II alpha-neurotoxin
All



The short-chain subfamily
This subfamily is composed of short 3FTs (57-66 amino acid residues) with four disulfide bonds and has usually only two residues before the first and after the last cysteine residues. The short-chain subfamily is subdivided in numerous sub-subfamilies, reflecting activity or geographical regroupment:

• Type I alpha-neurotoxin
• Type III alpha-neurotoxin
(unique to Australian elapids
(Jackson et al., 2013 ))
• Acn-esterase inhibitor
• Antiplatelet toxin
• Beta-cardiotoxin
• L-type calcium blocker
• Orphan group I
• Orphan group III
• Orphan group VII
• Orphan group VIII
(haditoxin)
• Orphan group IX
• Orphan group X
• Orphan group XI
• Orphan group XII
• Orphan group XIII
• Orphan group XIV
• Orphan group XV
• Orphan group XVI
• Orphan group XVIII
• Orphan group XX
• Aminergic (type A
muscarinic) toxin
• Type B muscarinic toxin
• Type C muscarinic toxin
• Type IA cytotoxin
• Type IB cytotoxin

All






The non-conventional subfamily
This subfamily was previously named “weak neurotoxin”, because of the weak toxicity of the first members of this subfamily. It is composed of 3FTs with a 5th disulfide bond in the first loop (Fig.1) and mature proteins of this subfamily contain 62-77 amino acid residues. Non-conventional 3FTs are subdivided in several sub-subfamilies:

• Boigatoxin
• Orphan group II
• Orphan group IV
• Orphan group V
• Orphan group VI
• Orphan group XVII
• Orphan group XIX

All



Monomers, dimers
3FTs are mostly monomers (see entries ), but a few covalent and non-covalent dimers (see entries ) have been described.