title: Conformational Heterogeneity of Bax Helix 9 Dimer for Apoptotic Pore Formation.
abstract: Helix α9 of Bax protein can dimerize in the mitochondrial outer membrane (MOM) and lead to apoptotic pores. However, it remains unclear how different conformations of the dimer contribute to the pore formation on the molecular level. Thus we have investigated various conformational states of the α9 dimer in a MOM model - using computer simulations supplemented with site-specific mutagenesis and crosslinking of the α9 helices. Our data not only confirmed the critical membrane environment for the α9 stability and dimerization, but also revealed the distinct lipid-binding preference of the dimer in different conformational states. In our proposed pathway, a crucial iso-parallel dimer that mediates the conformational transition was discovered computationally and validated experimentally. The corroborating evidence from simulations and experiments suggests that, helix α9 assists Bax activation via the dimer heterogeneity and interactions with specific MOM lipids, which eventually facilitate proteolipidic pore formation in apoptosis regulation.
authors.affiliation: Department of Chemistry, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Chenyi
authors.initials: C
authors.lastname: Liao
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.|Department of Biochemistry, McMaster University, Hamilton, ON, Canada.
authors.forename: Justin
authors.initials: J
authors.lastname: Kale
authors.affiliation: Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.|Department of Biochemistry, McMaster University, Hamilton, ON, Canada.|Departments of Biochemistry and Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Andrews
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA.|Stephenson Cancer Center, Oklahoma City, OK 73104, USA.
authors.forename: Jialing
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Chemistry, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Jianing
authors.initials: J
authors.lastname: Li
mesh_terms: D020816:Amino Acid Motifs; D017209:Apoptosis; D003198:Computer Simulation; D004220:Disulfides; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000737:chemistry* / Q000502:physiology*
chemical_list: C494772:BAK1 protein, human; C494826:BAX protein, human; D004220:Disulfides; D008055:Lipids; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein