Abstract
We report here the first three-dimensional structure of α-latrotoxin, a black widow spider neurotoxin, which forms membrane pores and stimulates secretion in the presence of divalent cations. We discovered that α-latrotoxin exists in two oligomeric forms: it is dimeric in EDTA but forms tetramers in the presence of Ca2+ or Mg2+. The dimer and tetramer structures were determined independently at 18 Å and 14 Å resolution, respectively, using cryo-electron microscopy and angular reconstitution. The α-latrotoxin monomer consists of three domains. The N- and C-terminal domains have been identified using antibodies and atomic fitting. The C4-symmetric tetramers represent the active form of α-latrotoxin; they have an axial channel and can insert into lipid bilayers with their hydrophobic base, providing the first model of α-latrotoxin pore formation.
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Acknowledgements
We thank R. Weinzierl for the use of the DLS spectrometer. The work was funded by a Wellcome Trust Senior European Research Fellowship (to Y.A.U.) and BBSRC and EC grants (to M.v.H.).
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Orlova, E., Rahman, M., Gowen, B. et al. Structure of α-latrotoxin oligomers reveals that divalent cation-dependent tetramers form membrane pores. Nat Struct Mol Biol 7, 48–53 (2000). https://doi.org/10.1038/71247
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DOI: https://doi.org/10.1038/71247
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