9GOA

Pore state of alpha-Latrotoxin

9GOA の概要

• エントリーDOI: 10.2210/pdb9goa/pdb
• EMDBエントリー: 51495
• 分子名称: Alpha-latrotoxin-Lt1a (1 entity in total)
• 機能のキーワード: black widow spider toxin, pore forming neurotoxin, ankyrin repeat, presynaptic receptor activation, toxin
• 由来する生物種: Latrodectus tredecimguttatus (black widow)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 526996.56

構造登録者

Klink, B.U.,Gatsogiannis, C.,Kalyankumar, K.S. (登録日: 2024-09-05, 公開日: 2024-10-16)

主引用文献

Klink, B.U.,Alavizargar, A.,Kalyankumar, K.S.,Chen, M.,Heuer, A.,Gatsogiannis, C.
Structural basis of alpha-latrotoxin transition to a cation-selective pore.
Nat Commun, 15:8551-8551, 2024

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 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.

PubMed: 39362850
DOI: 10.1038/s41467-024-52635-5

実験手法

ELECTRON MICROSCOPY (3.2 Å)