Structure of alpha-latrotoxin oligomers reveals that divalent cation-dependent tetramers form membrane pores |
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Authors: | Orlova E V Rahman M A Gowen B Volynski K E Ashton A C Manser C van Heel M Ushkaryov Y A |
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Institution: | Biochemistry Department, Imperial College, Exhibition Road, London SW7 2AY, UK. |
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Abstract: | We report here the first three-dimensional structure of alpha-latrotoxin, a black widow spider neurotoxin, which forms membrane pores and stimulates secretion in the presence of divalent cations. We discovered that alpha-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 A and 14 A resolution, respectively, using cryo-electron microscopy and angular reconstitution. The alpha-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 alpha-latrotoxin; they have an axial channel and can insert into lipid bilayers with their hydrophobic base, providing the first model of alpha-latrotoxin pore formation. |
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