7ptx
Alpha-latrocrustotoxin monomer
Structural highlights
Publication Abstract from PubMedLatrotoxins (LaTXs) are presynaptic pore-forming neurotoxins found in the venom of Latrodectus spiders. The venom contains a toxic cocktail of seven LaTXs, with one of them targeting vertebrates (alpha-latrotoxin (alpha-LTX)), five specialized on insects (alpha, beta, gamma, delta, epsilon- latroinsectotoxins (LITs), and one on crustaceans (alpha-latrocrustatoxin (alpha-LCT)). LaTXs bind to specific receptors on the surface of neuronal cells, inducing the release of neurotransmitters either by directly stimulating exocytosis or by forming Ca(2+)-conductive tetrameric pores in the membrane. Despite extensive studies in the past decades, a high-resolution structure of a LaTX is not yet available and the precise mechanism of LaTX action remains unclear. Here, we report cryoEM structures of the alpha-LCT monomer and the delta-LIT dimer. The structures reveal that LaTXs are organized in four domains. A C-terminal domain of ankyrin-like repeats shields a central membrane insertion domain of six parallel alpha-helices. Both domains are flexibly linked via an N-terminal alpha-helical domain and a small beta-sheet domain. A comparison between the structures suggests that oligomerization involves major conformational changes in LaTXs with longer C-terminal domains. Based on our data we propose a cyclic mechanism of oligomerization, taking place prior membrane insertion. Both recombinant alpha-LCT and delta-LIT form channels in artificial membrane bilayers, that are stabilized by Ca(2+) ions and allow calcium flux at negative membrane potentials. Our comparative analysis between alpha-LCT and delta-LIT provides first crucial insights towards understanding the molecular mechanism of the LaTX family. Molecular architecture of black widow spider neurotoxins.,Chen M, Blum D, Engelhard L, Raunser S, Wagner R, Gatsogiannis C Nat Commun. 2021 Nov 29;12(1):6956. doi: 10.1038/s41467-021-26562-8. PMID:34845192[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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