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

Genes & development | Aug 15, 2000

http://www.ncbi.nlm.nih.gov/pubmed/10950869

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.

Pubmed ID: 10950869 RIS Download

Mesh terms: Allosteric Regulation | Animals | BH3 Interacting Domain Death Agonist Protein | Biopolymers | Carrier Proteins | Cell Membrane | Cytochrome c Group | Membrane Proteins | Mice | bcl-2 Homologous Antagonist-Killer Protein

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Associated grants

  • Agency: NCI NIH HHS, Id: 5T32CA09361-19
  • Agency: NCI NIH HHS, Id: CA50239

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