BAK core dimers bind lipids and can be bridged by them

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• BAK (Bcl-2-associated X protein) and BAX (Bcl-2-associated agonist of cell death) are key proteins in apoptosis.
• These proteins oligomerize to permeabilize the mitochondrial outer membrane, a critical step in programmed cell death.
• A symmetric dimer intermediate is known, but secondary interfaces for oligomerization remain unidentified.

Purpose of the Study:

• To elucidate the structural basis of BAK oligomerization.
• To investigate the role of membrane lipids in BAK and BAX oligomerization.
• To identify potential sites for therapeutic intervention in apoptosis.

Main Methods:

• Crystal structure determination of human BAK core domain (α2-α5) dimers.
• Analysis of lipid and detergent binding sites.
• Structural modeling to propose a mechanism of lipid-mediated oligomerization.

Main Results:

• Crystal structures revealed preferred binding sites for membrane lipids and detergents on BAK core dimers.
• Lipids associate with BAK dimers, with specific interactions involving phospholipid headgroups and acyl chains (sn2 and sn1).
• A model suggests lipids bridge neighboring BAK dimers, facilitating oligomerization.

Conclusions:

• Unlike other pore-forming proteins, BAK and BAX oligomerization is significantly influenced by membrane lipids.
• The cell membrane itself plays an active role in the assembly of BAK/BAX pores.
• This finding offers new insights into the regulation of apoptosis and potential therapeutic strategies targeting BAK/BAX.