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  • 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.

Molecular cell (2020-06-14)
Zachary J Hauseman, Edward P Harvey, Catherine E Newman, Thomas E Wales, Joel C Bucci, Julian Mintseris, Devin K Schweppe, Liron David, Lixin Fan, Daniel T Cohen, Henry D Herce, Rida Mourtada, Yael Ben-Nun, Noah B Bloch, Scott B Hansen, Hao Wu, Steven P Gygi, John R Engen, Loren D Walensky
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.

MATERIALS
Product Number
Brand
Product Description

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