Three-Finger Toxins

There are over two dozen protein superfamilies that have been described in snake venoms, and three-finger toxins (3FTxs) are among the most abundant non-enzymatic venom components. All 3FTxs maintain a conserved structure of three β-stranded loops projecting outward from a central hydrophobic core, resembling three extended fingers of a hand. These toxins are small and usually occur as monomers, but they can also form dimers. Dozens of different 3FTx isoforms can be found in a single venom, and although all exhibit the same structural scaffold, they have diverse activities. Many characterized 3FTxs are α-neurotoxins, which have high affinity (K_d values of 10⁻⁹–10⁻¹¹ M) for nicotinic acetylcholine receptors and function as antagonists, leading to paralysis and respiratory arrest from snakebite. 3FTx receptor selectivity varies, even between receptor subtypes or receptors from different species. Besides neurotransmission, 3FTxs can interfere with processes such as blood coagulation or platelet aggregation. These toxins can also be cytotoxic, disrupting cell membranes by ion pore formation. Gene duplications within this toxin family, followed by amino acid residue substitutions, are responsible for the multitude of different isoforms and functions. For a few well-characterized 3FTxs, mutational studies have elucidated the functional amino acid residues for different target interactions. In this chapter, we present an overview of 3FTx structure and function relationships and detail the evolutionary mechanisms behind the generation of these versatile venom components.