Onset of anthrax toxin pore formation

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Protective antigen (PA) is a key component of anthrax toxin, interacting with the cellular receptor CMG2.
• PA-CMG2 complex formation is essential for host cell intoxication by anthrax.
• Pore formation by PA within the endosome membrane is a critical step in anthrax pathogenesis.

Purpose of the Study:

• To elucidate the molecular mechanism of PA-CMG2 complex destabilization at low pH.
• To understand the structural rearrangements leading to PA pore formation.
• To investigate the role of specific amino acid protonation in receptor-ligand binding dynamics.

Main Methods:

• Extensive molecular dynamics (MD) simulations were employed.
• Simulations involved large systems (over 92,000 atoms) and significant timescales (approx. 136 ns).
• Analysis focused on the PA-CMG2 complex under varying pH conditions.

Main Results:

• The PA-CMG2 complex is stable at neutral pH but destabilizes at acidic pH due to protonation of His-121 and Glu-122.
• Protonation disrupts a critical salt bridge, leading to the detachment of PA domain II.
• This destabilization releases a PA segment required for pore formation and explains the complex's stability via cation coordination.

Conclusions:

• The study reveals the pH-dependent mechanism of anthrax toxin activation at the molecular level.
• Understanding these interactions provides insights into blocking anthrax toxin entry.
• The findings highlight the importance of specific residues and cation coordination in receptor-ligand complex stability.