2. Academic Validation
  3. Homogeneous Oligomers of Pro-apoptotic BAX Reveal Structural Determinants of Mitochondrial Membrane Permeabilization

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.
Zachary J Hauseman 1,  Edward P Harvey 1,  Catherine E Newman 1,  Thomas E Wales 2,  Joel C Bucci 2,  Julian Mintseris 3,  Devin K Schweppe 3,  Liron David 4,  Lixin Fan 5,  Daniel T Cohen 1,  Henry D Herce 1,  Rida Mourtada 1,  Yael Ben-Nun 1,  Noah B Bloch 1,  Scott B Hansen 6,  Hao Wu 4,  Steven P Gygi 3,  John R Engen 2,  Loren D Walensky 7
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
  • 2 Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.
  • 3 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • 5 Small Angle X-ray Scattering Core, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
  • 6 The Scripps Research Institute-Florida, Jupiter, FL 33458, USA.
  • 7 Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address: [email protected].
PMID: 32533918 DOI: 10.1016/j.molcel.2020.05.029
Abstract

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.

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