title: An Autoinhibited Dimeric Form of BAX Regulates the BAX Activation Pathway.
abstract: 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.
authors.affiliation: Department of Biochemistry and Department of Medicine, Albert Einstein Cancer Center, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Garner
authors.affiliation: Department of Biochemistry and Department of Medicine, Albert Einstein Cancer Center, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Denis E
authors.initials: DE
authors.lastname: Reyna
authors.affiliation: Department of Biochemistry and Department of Medicine, Albert Einstein Cancer Center, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Priyadarshi
authors.affiliation: Human Oncology and Pathogenesis Program and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Chen
authors.affiliation: Department of Medicine and UCSD DXMS Proteomics Resource, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Department of Medicine, Albert Einstein Cancer Center, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Human Oncology and Pathogenesis Program and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yogesh Tengarai
authors.initials: YT
authors.lastname: Ganesan
authors.affiliation: Department of Biochemistry and Department of Biophysics and Physiology, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Malashkevich
authors.affiliation: Human Oncology and Pathogenesis Program and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Emily H
authors.initials: EH
authors.lastname: Cheng
authors.affiliation: Department of Biochemistry and Department of Medicine, Albert Einstein Cancer Center, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: evripidis.gavathiotis@einstein.yu.edu.
authors.forename: Evripidis
authors.initials: E
authors.lastname: Gavathiotis
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D003600:Cytosol / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014162:Transfection; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C494826:BAX protein, human; C494827:Bax protein, mouse; D051028:bcl-2-Associated X Protein