title: tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c.
abstract: TNFR1/Fas engagement results in the cleavage of cytosolic BID to truncated tBID, which translocates to mitochondria. Immunodepletion and gene disruption indicate BID is required for cytochrome c release. Surprisingly, the three-dimensional structure of this BH3 domain-only molecule revealed two hydrophobic alpha-helices suggesting tBID itself might be a pore-forming protein. Instead, we demonstrate that tBID functions as a membrane-targeted death ligand in which an intact BH3 domain is required for cytochrome c release, but not for targeting. Bak-deficient mitochondria and blocking antibodies reveal tBID binds to its mitochondrial partner BAK to release cytochrome c, a process independent of permeability transition. Activated tBID results in an allosteric activation of BAK, inducing its intramembranous oligomerization into a proposed pore for cytochrome c efflux, integrating the pathway from death receptors to cell demise.
authors.affiliation: Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Wei
authors.forename: T
authors.initials: T
authors.lastname: Lindsten
authors.forename: V K
authors.initials: VK
authors.lastname: Mootha
authors.forename: S
authors.initials: S
authors.lastname: Weiler
authors.forename: A
authors.initials: A
authors.lastname: Gross
authors.forename: M
authors.initials: M
authors.lastname: Ashiya
authors.forename: C B
authors.initials: CB
authors.lastname: Thompson
authors.forename: S J
authors.initials: SJ
authors.lastname: Korsmeyer
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein; D001704:Biopolymers; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D050998:bcl-2 Homologous Antagonist-Killer Protein
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494773:Bak1 protein, mouse; C494815:Bid protein, mouse; D001704:Biopolymers; D002352:Carrier Proteins; D003574:Cytochrome c Group; D008565:Membrane Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein