Fig. 5: Latrotoxin tetramer assembly prior membrane insertion.

a Simulated volume of a soluble δ-LIT insertion-competent tetramer. b Proposed model of latrotoxin action at the presynaptic membrane prior membrane insertion. The G-shaped toxin is activated upon cleavage of the 200aa C-terminal inhibitory domain. The present study reveals a characteristic bipolar charge distribution with the tail of the complex displaying a prominent negatively charged patch. We therefore propose that the toxin is orientated with its tail facing the positively charged outer surface of the presynaptic membrane (alternative scenarios canot be ruled out; see Supplementary Fig. 16). It is likely that toxin-receptor interactions trigger the oligomerization of the toxin and assembly of a competent prepore tetramer. The dimer is thereby first formed with the two protomers rotated 90 degrees relative to each other. The receptor-binding site is probably positioned at the C-terminal tail of the toxin (see “Discussion”). Structures of receptor-toxin complexes are however still lacking and further studies are now required to shed light into these interactions. Latrotoxins with longer C-terminal tails are expected to undergo large conformational changes during assembly of the prepore tetramer (see Discussion). Subsequently, a calcium selective pore is inserted into the presynaptic membrane, the underlying mechanism is however still unclear.