1.C.63 The α-Latrotoxin (Latrotoxin) Family The α-latrotoxin (αLTX) is a neurotoxin with 21 ANK repeats (residues 490-1199) from the venom of the black widow spider. It forms tetrameric cation selective pores in black lipid membranes with a subunit molecular weight of about 120 kDa. It binds to three distinct receptors in presynaptic plasma membranes of nerve terminals, activating synaptic vesicle exocytosis, probably due to Ca²⁺ influx and ATP depletion. The receptors are (1) a protein tyrosyl kinase, (2) a 1 TMS cell adhesion protein, and (3) a G-protein coupled receptor (Krasnoperov et al., 2002a,b). It is possible but not established that channel formation alone elicits the biological response. The α-latrotoxin precursor is 1401 aas long and has an N-terminal signal sequence. It may be processed both at its N- and C-termini. It shows extensive regions of sequence similarity to members of the Trp-CC family (TC #1.A.4) (25% identity between residues 628-1159 of Latrotoxin and residues 65-602 in ANKTM1 of Mus musculus (TC #1.A.4.6.1). Binding of the N terminus of alpha-LTX to one of its specific receptors may either trigger intracellular signaling cascades, resulting in phospholipase C-mediated mobilization of presynaptic Ca2 stores, or lead to the formation of tetrameric pore complexes, allowing extracellular Ca²⁺ to enter the presynaptic terminal. Alpha-LTX-triggered exocytosis and fulminant transmitter release at autonomic synapses may then provoke a clinical syndrome referred to as ''latrodectism'', characterized by local and incapacitating pain, diaphoresis, muscle fasciculation, tremors and anxiety (Luch 2010). It affects the mitochondrial membrane potential and the proton gradient across synaptic vesicles of nerve terminals (Tarasenko et al. 2008).
This family belongs to the Ankyrin Repeat Domain-containing (Ank) Superfamily.
References:
Chen, M., D. Blum, L. Engelhard, S. Raunser, R. Wagner, and C. Gatsogiannis. (2021). Molecular architecture of black widow spider neurotoxins. Nat Commun 12: 6956.
Dulubova, I.E., V.G. Krasnoperov, M.V. Khvotchev, K.A. Pluzhnikov, T.M. Volkova, E.V. Grishin, H. Vais, D.R. Bell, and P.N. Usherwood. (1996). Cloning and structure of δ-latroinsectotoxin, a novel insect-specific member of the latrotoxin family: functional expression requires C-terminal truncation. J. Biol. Chem. 271: 7535-7543.
Hurlbut, W.P., E. Chieregatti, F. Valtorta, and C. Haimann. (1994). Alpha-latrotoxin channels in neuroblastoma cells. J. Membr. Biol. 138: 91-102.
Krasnoperov, V., M.A. Bittner, W. Mo, L. Buryanovsky, T.A. Neubert, R.W. Holz, K. Ichtchenko, and A.G. Petrenko. (2002a). Protein-tyrosine phosphatase-σ is a novel member of the functional family of α-latrotoxin receptors. J. Biol. Chem. 277: 35887-35895.
Krasnoperov, V., Y. Lu, L. Buryanovsky, T.A. Neubert, K. Ichtchenko, and A.G. Petrenko. (2002b). Post-translational proteolytic processing of the calcium-independent receptor of α-latrotoxin (CIRL), a natural chimera of the cell adhesion protein and the G protein-coupled receptor. Role of the G protein-coupled receptor proteolysis site (GPS) motif. J. Biol. Chem. 277: 46518-46526.
Lajus, S., P. Vacher, D. Huber, M. Dubois, M.N. Benassy, Y. Ushkaryov, and J. Lang. (2006). Alpha-latrotoxin induces exocytosis by inhibition of voltage-dependent K⁺ channels and by stimulation of L-type Ca²⁺ channels via latrophilin in β-cells. J. Biol. Chem. 281: 5522-5531.
Luch, A. (2010). Mechanistic insights on spider neurotoxins. EXS. 100: 293-315.
Shatursky, O.Y., T.M. Volkova, N.H. Himmelreich, and E.V. Grishin. (2007). The geometry of the ionic chànnel lumen formed by α-latroinsectotoxin from black widow spider venom in the bilayer lipid membranes. Biochim. Biophys. Acta. 1768: 2757-2763.
Tarasenko, A.S., L.G. Storchak, and N.H. Himmelreich. (2008). α-Latrotoxin affects mitochondrial potential and synaptic vesicle proton gradient of nerve terminals. Neurochem Int 52: 392-400.
Examples:
TC#	Name	Organismal Type	Example
1.C.63.1.1	Spider venom α-latrotoxin of 1401 aas, α-LTX. It induces massive exocytosis after binding to a surface receptor, latrophilin (LPH). In this process, it first induced membrane depolarization by inhibition of repolarizing K⁺ channels followed by the appearance of Ca²⁺ transients. In a second phase, the toxin induced a large inward current and a prominent increase in intracellular calcium ions, reflecting pore formation (Lajus et al. 2006).	Spiders	α-latrotoxin from Latrodectus mactans

1.C.63.1.2	*α-latroinsectotoxin precursor (α-LIT) (1411aas) (Shatursky et al., 2007)*	Spiders	*α-LIT of Latrodectus mactans* (Q02989)**

1.C.63.1.3	α-latrocrustotoxin-Lt1a-like protein of 722 aas.		Lt1a of Parasteatoda tepidariorum

1.C.63.1.4	Delta-latroinsectotoxin-Lt1a of 1214 aas and 2 TMSs near the N-terminus. It is an insecticidal presynaptic neurotoxin that induces massive neurotransmitter release at insect (but not vertebrate) neuromuscular junctions. Native toxin forms cation-permeable pores (with high permeability to calcium) in lipid membranes of locust muscle membrane and artificial lipid bilayers (Chen et al. 2021, Dulubova et al. 1996). It may bind to insect neurexin-1 homolog, insect adhesion G protein-coupled receptor L1 homolog, and insect receptor-type tyrosine-protein phosphatase S homolog, and induces neurotransmitter exocytosis both by forming tetrameric pores in membranes and signaling via G protein-coupled receptor. Oligomerization is a process independent of divalent cations (Chen et al. 2021).		*Delta-latroinsectotoxin-Lt1a of Latrodectus tredecimguttatus* (Mediterranean black widow spider)**