9go9

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Prepore state of alpha-Latrotoxin

Structural highlights

9go9 is a 4 chain structure with sequence from Latrodectus tredecimguttatus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 2.7Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LATA_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 PubMed

The 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.

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References

  1. ↑ Ashton AC, Volynski KE, Lelianova VG, Orlova EV, Van Renterghem C, Canepari M, Seagar M, Ushkaryov YA. alpha-Latrotoxin, acting via two Ca2+-dependent pathways, triggers exocytosis of two pools of synaptic vesicles. J Biol Chem. 2001 Nov 30;276(48):44695-703. PMID:11572875 doi:10.1074/jbc.M108088200
  2. ↑ Krasnoperov V, Bittner MA, Mo W, Buryanovsky L, Neubert TA, Holz RW, Ichtchenko K, Petrenko AG. Protein-tyrosine phosphatase-sigma is a novel member of the functional family of alpha-latrotoxin receptors. J Biol Chem. 2002 Sep 27;277(39):35887-95. PMID:12110683 doi:10.1074/jbc.M205478200
  3. ↑ Capogna M, Volynski KE, Emptage NJ, Ushkaryov YA. The alpha-latrotoxin mutant LTXN4C enhances spontaneous and evoked transmitter release in CA3 pyramidal neurons. J Neurosci. 2003 May 15;23(10):4044-53. PMID:12764091 doi:10.1523/JNEUROSCI.23-10-04044.2003
  4. ↑ Davletov BA, Krasnoperov V, Hata Y, Petrenko AG, Südhof TC. High affinity binding of alpha-latrotoxin to recombinant neurexin I alpha. J Biol Chem. 1995 Oct 13;270(41):23903-5. PMID:7592578 doi:10.1074/jbc.270.41.23903
  5. ↑ Davletov BA, Shamotienko OG, Lelianova VG, Grishin EV, Ushkaryov YA. Isolation and biochemical characterization of a Ca2+-independent alpha-latrotoxin-binding protein. J Biol Chem. 1996 Sep 20;271(38):23239-45. PMID:8798521 doi:10.1074/jbc.271.38.23239
  6. ↑ Ichtchenko K, Khvotchev M, Kiyatkin N, Simpson L, Sugita S, Südhof TC. alpha-latrotoxin action probed with recombinant toxin: receptors recruit alpha-latrotoxin but do not transduce an exocytotic signal. EMBO J. 1998 Nov 2;17(21):6188-99. PMID:9799228 doi:10.1093/emboj/17.21.6188
  7. ↑ Klink BU, Alavizargar A, Kalyankumar KS, Chen M, Heuer A, Gatsogiannis C. Structural basis of α-latrotoxin transition to a cation-selective pore. Nat Commun. 2024 Oct 3;15(1):8551. PMID:39362850 doi:10.1038/s41467-024-52635-5

Contents


PDB ID 9go9

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