The venom of black widow spiders contains a cocktail of seven specific latrotoxins, but only one — α-latrotoxin — targets vertebrates, including humans. Chemists at the University of Münster have now deciphered the structure of α-latrotoxin before and after membrane insertion at near atomic resolution.
Cryo-EM structure of α-latrotoxin in two distinct tetrameric states. Image credit: Klink et al., doi: 10.1038/s41467-024-52635-5.
Latrotoxins are the main toxic components of the venom of black widow spiders (genus Latrodectus).
The venom includes the vertebrate-specific α-latrotoxin, five insecticidal toxins known as α, β, γ, δ, and ε-latroinsectotoxins, as well as one toxin specific to crustaceans.
“α-Latrotoxin interferes with the transmission of signals in the nervous system,” said University of Münster researcher Björn Klink and colleagues.
“As soon as α-latrotoxin binds to specific receptors of the synapses — the contacts between nerve cells or between nerve cells and muscles — calcium ions flow uncontrollably into the presynaptic membranes of the signaling cells.”
“This induces release of neurotransmitters, triggering strong muscle contractions and spasms.”
“Despite the apparent simplicity of this process, there is a highly complex mechanism behind it.”
In order to better understand the mechanism of calcium influx into the presynaptic membrane, the authors used high-performance cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) computer simulations.
They showed that α-latrotoxin undergoes a remarkable transformation when it binds to the receptor.
Part of the toxic molecule forms a stalk that penetrates the cell membrane like a syringe.
As a special feature, this stalk forms a small pore in the membrane that functions as a calcium channel.
The MD simulations revealed that calcium ions can flow into the cell through a selective gate located on the side directly above the pore.
“The toxin mimics the function of the calcium channels of the presynaptic membrane in a highly complex way,” said University of Münster researcher Christos Gatsogiannis.
“It therefore differs in every respect from all previously known toxins.”
“The new findings open up a wide range of potential applications.”
“Latrotoxins have considerable biotechnological potential, including the development of improved antidotes, treatments for paralysis and new biopesticides.”
The study was published in the journal Nature Communications.
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B.U. Klink et al. 2024. Structural basis of α-latrotoxin transition to a cation-selective pore. Nat Commun 15, 8551; doi: 10.1038/s41467-024-52635-5
Source : Breaking Science News