Sequence differences between BAX and BAK core domains manifest as differences in their interactions with lipids

Area of Science:

• Molecular Biology
• Cell Biology
• Structural Biology

Background:

• The B-cell lymphoma 2 (BCL2) protein family regulates programmed cell death (apoptosis) through the mitochondrial pathway.
• Key members BCL2-associated protein X (BAX) and BCL2 homologous antagonist killer (BAK) form oligomers to permeabilize mitochondria.
• Homo- and heterodimerization of BAX and BAK are critical intermediate steps in their activation.

Purpose of the Study:

• To elucidate the structural basis of BAX homo-dimerization at atomic resolution.
• To investigate the potential interactions between BAX dimers and membrane lipids.
• To compare the lipid-binding properties of BAX and BAK by examining their heterodimers.

Main Methods:

• X-ray crystallography was used to determine the structures of BAX core domain dimers (helices α2-α5).
• Structures of BAK/BAX core domain heterodimers were also determined.
• Analysis of structural data to understand protein-protein and protein-lipid interactions.

Main Results:

• Crystal structures reveal the atomic details of BAX homo-dimer formation.
• Insights into how BAX dimers may interact with membrane lipids were obtained.
• Differences in lipid-interacting sites between BAX and BAK were identified, explaining distinct lipid-binding behaviors.

Conclusions:

• The structures provide a detailed understanding of BAX homo-dimerization, a key step in apoptosis.
• BAX and BAK exhibit distinct lipid-interaction mechanisms, influencing their roles in mitochondrial outer membrane permeabilization.
• These findings contribute to understanding the molecular mechanisms of programmed cell death.