Homogeneous Oligomers of Pro-apoptotic BAX Reveal Structural Determinants of Mitochondrial Membrane Permeabilization

Mol Cell. 2020 Jul 2;79(1):68-83.e7. doi: 10.1016/j.molcel.2020.05.029. Epub 2020 Jun 12.


BAX is a pro-apoptotic protein that transforms from a cytosolic monomer into a toxic oligomer that permeabilizes the mitochondrial outer membrane. How BAX monomers assemble into a higher-order conformation, and the structural determinants essential to membrane permeabilization, remain a mechanistic mystery. A key hurdle has been the inability to generate a homogeneous BAX oligomer (BAXO) for analysis. Here, we report the production and characterization of a full-length BAXO that recapitulates physiologic BAX activation. Multidisciplinary studies revealed striking conformational consequences of oligomerization and insight into the macromolecular structure of oligomeric BAX. Importantly, BAXO enabled the assignment of specific roles to particular residues and α helices that mediate individual steps of the BAX activation pathway, including unexpected functionalities of BAX α6 and α9 in driving membrane disruption. Our results provide the first glimpse of a full-length and functional BAXO, revealing structural requirements for the elusive execution phase of mitochondrial apoptosis.

Keywords: BAX; BCL-2 family; activation; alpha-helix; apoptosis; membrane permeabilization; mitochondria; monomer; oligomer; structure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis*
  • Biological Transport
  • Cell Membrane Permeability
  • Cytosol / metabolism
  • Humans
  • Mice
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mitochondrial Membranes / metabolism*
  • Models, Molecular
  • Protein Conformation
  • Protein Multimerization*
  • Proto-Oncogene Proteins c-fos
  • bcl-2-Associated X Protein / chemistry*
  • bcl-2-Associated X Protein / metabolism*


  • Proto-Oncogene Proteins c-fos
  • bcl-2-Associated X Protein