title: Assembly of Bak homodimers into higher order homooligomers in the mitochondrial apoptotic pore.
abstract: In mitochondrial apoptosis, Bak is activated by death signals to form pores of unknown structure on the mitochondrial outer membrane via homooligomerization. Cytochrome c and other apoptotic factors are released from the intermembrane space through these pores, initiating downstream apoptosis events. Using chemical crosslinking and double electron electron resonance (DEER)-derived distance measurements between specific structural elements in Bak, here we clarify how the Bak pore is assembled. We propose that previously described BH3-in-groove homodimers (BGH) are juxtaposed via the 'α3/α5' interface, in which the C-termini of helices α3 and α5 are in close proximity between two neighboring Bak homodimers. This interface is observed concomitantly with the well-known 'α6:α6' interface. We also mapped the contacts between Bak homodimers and the lipid bilayer based on EPR spectroscopy topology studies. Our results suggest a model for the lipidic Bak pore, whereby the mitochondrial targeting C-terminal helix does not change topology to accommodate the lining of the pore lumen by BGH.
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA.
authors.forename: Tirtha
authors.initials: T
authors.lastname: Mandal
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA.
authors.forename: Seungjin
authors.initials: S
authors.lastname: Shin
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA.
authors.forename: Sreevidya
authors.initials: S
authors.lastname: Aluvila
authors.affiliation: Human Oncology and Pathogenesis Program and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA.
authors.forename: Carter
authors.initials: C
authors.lastname: Grieve
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA.
authors.forename: Jun-Yong
authors.initials: JY
authors.lastname: Choe
authors.affiliation: Human Oncology and Pathogenesis Program and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Emily H
authors.initials: EH
authors.lastname: Cheng
authors.affiliation: Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Hustedt
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA.
authors.forename: Kyoung Joon
authors.initials: KJ
authors.lastname: Oh
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004578:Electron Spin Resonance Spectroscopy; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D008051:Lipid Bilayers / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C494773:Bak1 protein, mouse; D008051:Lipid Bilayers; D050998:bcl-2 Homologous Antagonist-Killer Protein