Three-finger proteins from snakes and humans acting on nicotinic receptors: Old and new

The first toxin to give rise to the three-finger protein (TFP) family was alpha-bungarotoxin (alpha-Bgt) from Bungarus multicinctus krait venom. alpha-Bgt was crucial for research on nicotinic acetylcholine receptors (nAChRs), and in this Review article we focus on present data for snake venom TFPs and those of the Ly6/uPAR family from mammalians (membrane-bound Lynx1 and secreted SLURP-1) interacting with nAChRs. Recently isolated from Bungarus candidus venom, alpha delta-bungarotoxins differ from alpha-Bgt: they bind more reversibly and distinguish two binding sites in Torpedo californica nAChR. Naja kaouthia alpha-cobratoxin, classical blocker of nAChRs, was shown to inhibit certain GABA-A receptor subtypes, whereas alpha-cobratoxin dimer with 2 intermolecular disulfides has a novel type of 3D structure. Non-conventional toxin WTX has additional 5th disulfide not in the central loop, as alpha-Bgt, but in the N-terminal loop, like all Ly6/uPAR proteins, and inhibits alpha 7 and Torpedo nAChRs. A water-soluble form of Lynx1, ws-Lynx1, was expressed inE.coli, its H-1-NMR structure and binding to several nAChRs determined. For SLURP-1, similar information was obtained with its recombinant analogue rSLURP-1. A common feature of ws-Lynx1, rSLURP-1, and WTX is their activity against nAChRs and muscarinic acetylcholine receptors. Synthetic SLURP-1, identical to the natural protein, demonstrated some differences from rSLURP-1 in distinguishing nAChR subtypes. The loop II fragment of the Lynx1 was synthesized having the same mu M affinity for the Torpedo nAChR as ws-Lynx1. This review illustrates the productivity of parallel research of nAChR interactions with the two TFP groups.

Automated summary

This review focuses on the interactions of snake venom TFPs and Ly6/uPAR family proteins from mammals with nicotinic acetylcholine receptors (nAChRs), highlighting the different characteristics of various toxins and their interactions with different receptor subtypes.