Structural basis of α-latrotoxin transition to a cation-selective pore

B. U. Klink, A. Alavizargar, K. S. Kalyankumar, M. Chen, A. Heuer () and C. Gatsogiannis ()
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B. U. Klink: University Münster
A. Alavizargar: University Münster
K. S. Kalyankumar: University Münster
M. Chen: University Münster
A. Heuer: University Münster
C. Gatsogiannis: University Münster

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract The potent neurotoxic venom of the black widow spider contains a cocktail of seven phylum-specific latrotoxins (LTXs), but only one, α-LTX, targets vertebrates. This 130 kDa toxin binds to receptors at presynaptic nerve terminals and triggers a massive release of neurotransmitters. It is widely accepted that LTXs tetramerize and insert into the presynaptic membrane, thereby forming Ca2+-conductive pores, but the underlying mechanism remains poorly understood. LTXs are homologous and consist of an N-terminal region with three distinct domains, along with a C-terminal domain containing up to 22 consecutive ankyrin repeats. Here we report cryoEM structures of the vertebrate-specific α-LTX tetramer in its prepore and pore state. Our structures, in combination with AlphaFold2-based structural modeling and molecular dynamics simulations, reveal dramatic conformational changes in the N-terminal region of the complex. Four distinct helical bundles rearrange and together form a highly stable, 15 nm long, cation-impermeable coiled-coil stalk. This stalk, in turn, positions an N-terminal pair of helices within the membrane, thereby enabling the assembly of a cation-permeable channel. Taken together, these data give insight into a unique mechanism for membrane insertion and channel formation, characteristic of the LTX family, and provide the necessary framework for advancing novel therapeutics and biotechnological applications.

Date: 2024
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DOI: 10.1038/s41467-024-52635-5

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