Receptor binding enables botulinum neurotoxin B to sense low pH for translocation channel assembly.

Abstract

Botulinum neurotoxins (BoNTs, serotypes A-G), elaborated by Clostridium botulinum, can induce lethal paralysis and are classified as Category A bioterrorism agents. However, how BoNTs translocate from endosomes into the cytosol of neurons to gain access to their intracellular targets remains enigmatic. We discovered that binding to the ganglioside GT1b, a toxin coreceptor, enables BoNT/B to sense low pH, undergo a significant change in secondary structure, and transform into a hydrophobic oligomeric membrane protein. Imaging of the toxin on lipid bilayers using atomic force microscopy revealed donut-shaped channel-like structures that resemble other protein translocation assemblies. Toosendanin, a drug with therapeutic effects against botulism, inhibited GT1b-dependent BoNT/B oligomerization and in parallel truncated BoNT/B single-channel conductance, suggesting that oligomerization plays a role in the translocation reaction. Thus, BoNT/B functions as a coincidence detector for receptor and low pH to ensure spatial and temporal accuracy for toxin conversion into a translocation channel.

• Authors: Shihu Sun, Swetha Suresh, Huisheng Liu, William H Tepp, Eric A Johnson, J Michael Edwardson, Edwin R Chapman
• Journal: Cell host & microbe (Cell Host Microbe) Vol. 10 Issue 3 Pg. 237-47 (Sep 15 2011) ISSN: 1934-6069 [Electronic] United States
• PMID: 21925111 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Gangliosides
• Receptors, Cell Surface
• rimabotulinumtoxinB
• trisialoganglioside GT1
• Botulinum Toxins
• Botulinum Toxins, Type A

Topics

• Animals
• Binding Sites
• Botulinum Toxins (chemistry, genetics, metabolism)
• Botulinum Toxins, Type A
• Botulism (genetics, metabolism, microbiology)
• Cell Membrane (metabolism, microbiology)
• Clostridium botulinum (chemistry, genetics, metabolism)
• Gangliosides (metabolism)
• Humans
• Hydrogen-Ion Concentration
• Mice
• Mice, Knockout
• Protein Binding
• Protein Multimerization
• Protein Structure, Secondary
• Protein Transport
• Receptors, Cell Surface (genetics, metabolism)