Botulinum neurotoxins B and E translocate at different rates and exhibit divergent responses to GT1b and low pH.
Botulinum neurotoxins (BoNTs, serotypes A-G) are the most deadly substances known. Here, we investigated how BoNT/E, a serotype that causes human botulism, translocates into the cytosol of neurons. Analogous to BoNT/B, BoNT/E required binding of the coreceptor, GT1b, to undergo significant secondary structural changes and transform into a hydrophobic protein at low pH. These data indicate that both serotypes act as coincidence detectors for both GT1b and low pH, to undergo translocation. However, BoNT/E translocated much more rapidly than BoNT/B. Also, BoNT/E required only GT1b, and not low pH, to oligomerize, whereas BoNT/B required both. In further contrast to the case of BoNT/B, low pH alone altered the secondary structure of BoNT/E to some degree and resulted in its premature inactivation. Hence, comparison of two BoNT serotypes revealed that these agents exhibit both convergent and divergent responses to receptor interactions, and pH, in the translocation pathway.
Howard Hughes Medical Institute.
Shihu
S
Sun
William H
WH
Tepp
Eric A
EA
Johnson
Edwin R
ER
Chapman
D000818:Animals; D001905:Botulinum Toxins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019274:Botulinum Toxins, Type A; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D005732:Gangliosides / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D018942:Macrolides / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D021381:Protein Transport; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D051381:Rats
D005732:Gangliosides; D018942:Macrolides; C096323:rimabotulinumtoxinB; C016481:trisialoganglioside GT1; C036978:concanamycin A; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A; D006180:Proton-Translocating ATPases; C096326:botulinum toxin type E