9go9 | pdb_00009go9
Prepore state of alpha-Latrotoxin
Structural highlights
FunctionLATA_LATTR Presynaptic neurotoxin that causes massive release of neurotransmitters from vertebrate (but not invertebrate) nerve terminals and endocrine cells via a complex mechanism involving activation of receptor(s) and toxin insertion into the plasma membrane with subsequent pore formation. Binds to neurexin-1-alpha (NRXN1) in a calcium dependent manner, adhesion G protein-coupled receptor L1 (ADGRL1, also termed latrophilin-1 and calcium-independent receptor of latrotoxin (CIRL)), and receptor-type tyrosine-protein phosphatase S (PTPRS), also termed PTP sigma (PubMed:12110683, PubMed:7592578, PubMed:8798521). NRXN1 and PTPRS are suggested to provide a platform for binding and subsequent pore formation events (PubMed:11572875, PubMed:9799228). In contrast, binding to ADGRL1 does not involve oligomerization and channel formation, but direct downstream stimulation of the synaptic fusion machinery (PubMed:12764091).[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe potent neurotoxic venom of the black widow spider contains a cocktail of seven phylum-specific latrotoxins (LTXs), but only one, alpha-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(2+)-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 alpha-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. Structural basis of alpha-latrotoxin transition to a cation-selective pore.,Klink BU, Alavizargar A, Kalyankumar KS, Chen M, Heuer A, Gatsogiannis C Nat Commun. 2024 Oct 3;15(1):8551. doi: 10.1038/s41467-024-52635-5. PMID:39362850[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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