Allostery in BAX protein activation

Area of Science:

• Molecular Biology
• Cellular Biology
• Biochemistry

Background:

• BAX protein, a key player in the BCL-2 family, regulates the intrinsic apoptosis pathway.
• Apoptosis involves BAX activation by BH3-only molecules, leading to mitochondrial outer membrane insertion, oligomerization, and cytochrome c release.

Purpose of the Study:

• To elucidate the intramolecular signal transmission pathway in BAX from BIM SAHB ligand binding to the mobilization of its alpha-helix.
• To gain a molecular understanding of BAX activation, a critical early step in apoptosis.

Main Methods:

• Microsecond atomistic molecular dynamics simulations of BAX protein and the BAX:BIM SAHB complex.
• Analysis of force distribution to identify residue-residue interaction networks responsible for signal transmission.

Main Results:

• BIM SAHB binding induces a more solvent-exposed conformation of the 6A7 epitope and BH3 domain.
• BIM SAHB binding stabilizes the secondary structure of the BAX alpha-9 helix.
• Force distribution analysis identified a network transmitting signals from the BIM SAHB binding site via alpha-4 and alpha-6 helices to the alpha-9 helix.

Conclusions:

• The study provides a detailed molecular mechanism for BAX activation by BIM SAHB.
• Understanding this signal transmission pathway is crucial for comprehending the initial events of apoptosis.