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| Title | Structural basis of α-latrotoxin transition to a cation-selective pore. |
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| Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 8551, Year 2024 |
| Publish date | Oct 3, 2024 |
 Authors | B U Klink / A Alavizargar / K S Kalyankumar / M Chen / A Heuer / C Gatsogiannis /  |
| PubMed 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 ...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 Ca-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. |
 External links | Nat Commun / PubMed:39362850 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.7 - 6.7 Å |
| Structure data |  EMDB-51465: Focussed refinement on alpha-Latrotoxin, ChainA, residues 796-1195  EMDB-51467: Focussed refinement on alpha-Latrotoxin, ChainA, residues 1-795  EMDB-51468: Focussed refinement on alpha-Latrotoxin, ChainB, residues 1-795  EMDB-51469: Focussed refinement on alpha-Latrotoxin, ChainB, residues 796-1195  EMDB-51472: Focussed refinement on alpha-Latrotoxin, ChainC, residues 1-795  EMDB-51473: Focussed refinement on alpha-Latrotoxin, ChainC, residues 796-1195  EMDB-51474: Focussed refinement on alpha-Latrotoxin, ChainD, residues 1-795  EMDB-51475: Focussed refinement on alpha-Latrotoxin, ChainD, residues 796-1195  EMDB-51476: Focussed refinement on alpha-Latrotoxin, ChainA-D, residues 105-788  EMDB-51479: Focussed refinement on alpha-Latrotoxin (Pore-state), chainA, residues 650-1195  EMDB-51484: Focussed refinement on alpha-Latrotoxin (Pore-state), chainC, residues 650-1195  EMDB-51485: Focussed refinement on alpha-Latrotoxin (Pore-state), chainB, residues 650-1195  EMDB-51488: Focussed refinement on alpha-Latrotoxin (Pore-state), chainD, residues 650-1195  EMDB-51490: Consensus refinement on alpha-Latrotoxin (Pore-state)  EMDB-51492: Consensus refinement on alpha-Latrotoxin (Prepore state) EMDB-51494: Prepore state of alpha-Latrotoxin (hybrid map) EMDB-51495, PDB-9goa: |
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 Keywords | TOXIN / Black widow spider toxin / Pore forming neurotoxin / Ankyrin repeat / presynaptic receptor activation |
latrodectus tredecimguttatus (black widow)