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Channels formed in phospholipid bilayer membranes by diphtheria, tetanus, botulinum and anthrax toxin
1Department of Physiology & Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461.
Abstract:
Diphtheria, tetanus, botulinum, and anthrax toxin are multipartate toxins, one of the domains of which is (or is presumed to be) an enzyme. Cell intoxication requires that the enzymatic portion gain access to the cytosol via endocytosis into an acidic vesicle compartment of the cell. Translocation of the enzyme across the vesicular membrane is dependent on the low pH of the vesicle and involves another domain of the toxin; for each of these toxins, that domain is capable of forming channels in phospholipid bilayer membranes. These channels are large (greater than 12 A diameter) and voltage-gated, and the pH conditions required for their formation in lipid bilayers are similar to those existing in acidic vesicles and required for cell intoxication.
Insights
Multipartate toxins like diphtheria and anthrax toxin use a channel-forming domain to translocate their enzymatic portion into host cells. This process, crucial for cell intoxication, depends on acidic vesicle pH and voltage-gated membrane channels.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Diphtheria, tetanus, botulinum, and anthrax toxins are multipartate toxins.
- Cell intoxication by these toxins requires enzymatic domain translocation into the cytosol.
- This translocation occurs via endocytosis into acidic vesicles.
Purpose of the Study:
- To elucidate the mechanism of enzymatic domain translocation across vesicular membranes.
- To investigate the role of a specific toxin domain in membrane channel formation.
- To correlate channel formation conditions with cellular intoxication requirements.
Main Methods:
- Analysis of toxin structure-function relationships.
- Lipid bilayer reconstitution assays.
- Electrophysiological measurements of membrane channels.
- pH-dependent activity assays.
Main Results:
- A specific toxin domain forms large (greater than 12 A diameter), voltage-gated channels in phospholipid bilayers.
- Channel formation is dependent on low pH conditions.
- These conditions mimic those found in acidic vesicles during intoxication.
Conclusions:
- The channel-forming domain facilitates enzyme translocation across the vesicular membrane.
- Low pH and voltage gating are critical for toxin-mediated cell intoxication.
- Understanding these channels is key to developing antitoxins.