tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c

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 hydr...

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Bibliographic Details
Published in:Genes & development 2000-08, Vol.14 (16), p.2060-2071
Main Authors: Wei, M C, Lindsten, T, Mootha, V K, Weiler, S, Gross, A, Ashiya, M, Thompson, C B, Korsmeyer, S J
Format: Article
Language:English
Subjects:
Allosteric Regulation
Animals
BAK protein
bcl-2 Homologous Antagonist-Killer Protein
BH3 Interacting Domain Death Agonist Protein
BID protein
Biopolymers
Carrier Proteins - metabolism
Cell Membrane - metabolism
cytochrome c
Cytochrome c Group - metabolism
death receptors
Membrane Proteins - metabolism
Mice
Research Paper
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Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.14.16.2060