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Receptor-specific requirements for anthrax toxin delivery into cells
G Jonah A Rainey1, Darran J Wigelsworth, Patricia L Ryan
1Infectious Disease Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Summary
Anthrax toxin
Area of Science:
- Biochemistry
- Cell Biology
- Toxicology
Background:
- Anthrax toxin comprises three proteins that assemble into toxic complexes.
- Protective antigen (PA) binds to cellular receptors TEM8 or CMG2, initiating toxin entry.
- Acidic endosomal pH triggers PA pore formation and catalytic subunit translocation.
Purpose of the Study:
- To investigate the influence of TEM8 and CMG2 receptors on anthrax toxin pore formation and translocation.
- To determine the pH thresholds for these events with different receptors.
- To elucidate the role of receptor binding affinity in toxin activity.
Main Methods:
- Comparative analysis of pH-dependent pore formation and translocation using TEM8 and CMG2 receptors.
- Assessment of sensitivity to ammonium chloride treatment in cells.
- Investigation of PA dissociation from receptors upon pore formation.
Main Results:
- The pH threshold for PA pore formation and translocation differs by approximately one pH unit between TEM8 and CMG2 receptors.
- TEM8-mediated toxin events occur at near-neutral pH with low ammonium chloride sensitivity.
- CMG2-mediated events require more acidic conditions and are highly sensitive to ammonium chloride.
Conclusions:
- PA dissociation from receptors is crucial for translocation, dependent on pore formation.
- Higher CMG2 binding affinity necessitates lower pH for PA dissociation and pore formation.
- Anthrax toxin can form pores at different endocytic pathway stages based on the specific receptor used.