An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway

• Published in: Molecular cell Vol. 63; no. 3; pp. 485 - 497
• Main Authors: Garner, Thomas P., Reyna, Denis E., Priyadarshi, Amit, Chen, Hui-Chen, Li, Sheng, Wu, Yang, Ganesan, Yogesh Tengarai, Malashkevich, Vladimir N., Cheng, Emily H., Gavathiotis, Evripidis
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.08.2016; Cell Press - Elsevier
• Subjects: Animals; Apoptosis; BASIC BIOLOGICAL SCIENCES; bcl-2-Associated X Protein - chemistry; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Binding Sites; Cells, Cultured; Crystallography, X-Ray; Cytosol - metabolism; Fibroblasts - metabolism; Humans; Mice; Models, Molecular; Protein Binding; Protein Conformation, alpha-Helical; Protein Interaction Domains and Motifs; Protein Multimerization; Signal Transduction; Structure-Activity Relationship; Transfection
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2016.06.010

Pro-apoptotic BAX is a cell fate regulator playing an important role in cellular homeostasis and pathological cell death. BAX is predominantly localized in the cytosol, where it has a quiescent monomer conformation. Following a pro-apoptotic trigger, cytosolic BAX is activated and translocates to the mitochondria to initiate mitochondrial dysfunction and apoptosis. Here, cellular, biochemical, and structural data unexpectedly demonstrate that cytosolic BAX also has an inactive dimer conformation that regulates its activation. The full-length crystal structure of the inactive BAX dimer revealed an asymmetric interaction consistent with inhibition of the N-terminal conformational change of one protomer and the displacement of the C-terminal helix α9 of the second protomer. This autoinhibited BAX dimer dissociates to BAX monomers before BAX can be activated. Our data support a model whereby the degree of apoptosis induction is regulated by the conformation of cytosolic BAX and identify an unprecedented mechanism of cytosolic BAX inhibition. [Display omitted] •BAX forms inactive dimers in the cytosol•Structure of the BAX dimer reveals a novel autoinhibition mechanism•Inactive BAX dimer dissociates to BAX monomers before BAX is activated•Autoinhibited dimer regulates BAX activation and BAX-mediated apoptosis Cytosolic BAX is thought to be a monomer that is activated by BH3-only proteins to induce cell death. Garner et al. show that cytosolic BAX can form a homo-dimer whose structure inhibits BAX activation, revealing a step in the regulation of BAX that modulates apoptosis.