Journal
EMBO JOURNAL
Volume 40, Issue 14, Pages -Publisher
WILEY
DOI: 10.15252/embj.2020106438
Keywords
bax core dimer; functional mutagenesis; membrane lipid bilayer; NMR structure; pore formation
Categories
Funding
- National Key R&D Program of China [2017YFA0504804]
- Key Research Program of Frontier Sciences, CAS [QYZDB-SSW-SMC043]
- US National Institutes of Health [R01GM062964]
- OCAST [HR16-026]
- Presbyterian Health Foundation
- Institutional Development Award from the National Institute of General Medical Sciences of US National Institutes of Health [P20GM103640]
- Canadian Institutes of Health Research [FDN 143312]
- Tier 1 Canada Research Chair in Membrane Biogenesis
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Bax proteins form pores in the mitochondrial outer membrane to initiate apoptosis. The high-resolution structure of the Bax core region revealed a dimer with specific surface interactions with lipid bilayers, suggesting its role in forming the pore wall during apoptosis. Structural mutations further confirmed the importance of protein-lipid interactions in Bax pore assembly.
Bax proteins form pores in the mitochondrial outer membrane to initiate apoptosis. This might involve their embedding in the cytosolic leaflet of the lipid bilayer, thus generating tension to induce a lipid pore with radially arranged lipids forming the wall. Alternatively, Bax proteins might comprise part of the pore wall. However, there is no unambiguous structural evidence for either hypothesis. Using NMR, we determined a high-resolution structure of the Bax core region, revealing 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 also creating polar interactions between charged residues and lipid heads. Structure-guided mutations demonstrate the importance of both types of 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.
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