title: Structural model of active Bax at the membrane.
abstract: Bax plays a central role in the mitochondrial pathway of apoptosis. Upon activation, cytosolic Bax monomers oligomerize on the surface of mitochondria and change conformation concertedly to punch holes into the outer membrane. The subsequent release of cytochrome c initiates cell death. However, the structure of membrane-inserted Bax and its mechanism of action remain largely unknown. Here, we propose a 3D model of active Bax at the membrane based on double electron-electron resonance (DEER) spectroscopy in liposomes and isolated mitochondria. We show that active Bax is organized at the membrane as assemblies of dimers. In addition to a stable dimerization domain, each monomer contains a more flexible piercing domain involved in interdimer interactions and pore formation. The most important structural change during Bax activation is the opening of the hairpin formed by helices 5 and 6, which adopts a clamp-like conformation central to the mechanism of mitochondrial permeabilization.
authors.affiliation: Max Planck Institute for Intelligent Systems, Heisenbergstrasse 3, 70569 Stuttgart, Germany; German Cancer Research Center, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany; Interfaculty Institute of Biochemistry, Eberhard Karls University Tübingen, Hoppe-Seyler-Strasse 4, 72076 Tübingen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bleicken
authors.affiliation: Laboratory of Physical Chemistry, ETH Zurich, Vladimir-Prelog-Weg 2, 8093 Zurich, Switzerland.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Jeschke
authors.affiliation: Max Planck Institute for Intelligent Systems, Heisenbergstrasse 3, 70569 Stuttgart, Germany; German Cancer Research Center, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany; Interfaculty Institute of Biochemistry, Eberhard Karls University Tübingen, Hoppe-Seyler-Strasse 4, 72076 Tübingen, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Stegmueller
authors.affiliation: Max Planck Institute for Intelligent Systems, Heisenbergstrasse 3, 70569 Stuttgart, Germany; German Cancer Research Center, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany; Interfaculty Institute of Biochemistry, Eberhard Karls University Tübingen, Hoppe-Seyler-Strasse 4, 72076 Tübingen, Germany.
authors.forename: Raquel
authors.initials: R
authors.lastname: Salvador-Gallego
authors.affiliation: Max Planck Institute for Intelligent Systems, Heisenbergstrasse 3, 70569 Stuttgart, Germany; German Cancer Research Center, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany; Interfaculty Institute of Biochemistry, Eberhard Karls University Tübingen, Hoppe-Seyler-Strasse 4, 72076 Tübingen, Germany. Electronic address: ana.garcia@uni-tuebingen.de.
authors.forename: Ana J
authors.initials: AJ
authors.lastname: García-Sáez
authors.affiliation: Laboratory of Physical Chemistry, ETH Zurich, Vladimir-Prelog-Weg 2, 8093 Zurich, Switzerland; Fachbereich Physik, Freie Universität Berlin, Arnimallee 14, 14195 Berlin, Germany. Electronic address: enrica.bordignon@fu-berlin.de.
authors.forename: Enrica
authors.initials: E
authors.lastname: Bordignon
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051028:bcl-2-Associated X Protein / Q000737:chemistry*
chemical_list: D051028:bcl-2-Associated X Protein