EMD-51467

Single-particle
2.75 Å
EMD-51467 Deposition: 02/09/2024
Map released: 16/10/2024
Last modified: 16/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-51467

Focussed refinement on alpha-Latrotoxin, ChainA, residues 1-795

EMD-51467

Single-particle
2.75 Å
EMD-51467 Deposition: 02/09/2024
Map released: 16/10/2024
Last modified: 16/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Latrodectus tredecimguttatus
Sample: tetrameric complex of alpha-latrotoxin

Deposition Authors: Klink BU , Gatsogiannis C , Kalyankumar KS
Structural basis of alpha-latrotoxin transition to a cation-selective pore.
Klink BU , Alavizargar A , Kalyankumar KS , Chen M , Heuer A , Gatsogiannis C
(2024) Nat Commun , 15 , 8551 - 8551
PUBMED: 39362850
DOI: doi:10.1038/s41467-024-52635-5
ISSN: 2041-1723
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.