Amphipathic Bax core dimer forms part of apoptotic pore wall in the mitochondrial membrane

Abstract

SummaryBax proteins form pores in the mitochondrial outer membrane to initiate apoptosis. They may embed in the cytosolic leaflet of the lipid bilayer generating tension to induce a lipid pore with radially arranged lipids forming the wall. Alternatively, they may comprise part of the pore wall. However, there is no unambiguous structural evidence for either hypothesis. Using NMR, we determine a high-resolution structure of the Bax core region that forms a dimer with the nonpolar surface covering the lipid bilayer edge and the polar surface exposed to water. The dimer tilts from the bilayer normal, not only maximizing nonpolar interactions with lipid tails but creating polar interactions between charged residues and lipid heads. Structure-guided mutations demonstrate the importance of both protein-lipid interactions in Bax pore assembly and core dimer configuration. Therefore, the Bax core dimer forms part of the proteolipid pore wall to permeabilize mitochondria.

The conformational stability of pro-apoptotic BAX is dictated by discrete residues of the protein core

“…A dimeric species of BAX α2-α5 was proposed to function as an essential subunit of homo-oligomerization 30 and a crystal structure of the dimeric truncate (GFP-BAX α2-α5) was subsequently solved 11 . Most recently, NMR analysis of this dimeric species (tagless) in bicelles delineated portions of BAX α2-α5 that can directly engage membrane lipids 31 . The specific amino acid interactions of BAX 113-116 are distinct in the latent, full-length monomer and the dimeric BAX α2-α5 complex (Figs.…”