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PMID: 10950869 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

Genes & development ·Vol. 14 ·No. 16 ·2000-08-15 ·Pages 2060-71

Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ

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.

MeSH Terms
Allosteric Regulation Animals BH3 Interacting Domain Death Agonist Protein Biopolymers Carrier Proteins/metabolism Cell Membrane/metabolism Cytochrome c Group/metabolism Membrane Proteins/metabolism Mice bcl-2 Homologous Antagonist-Killer Protein
Chemicals
BH3 Interacting Domain Death Agonist Protein Bak1 protein, mouse Bid protein, mouse Biopolymers Carrier Proteins Cytochrome c Group Membrane Proteins bcl-2 Homologous Antagonist-Killer Protein
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Wei M C
Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
Lindsten T
Mootha V K
Weiler S
Gross A
Ashiya M
Thompson C B
Korsmeyer S J
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
Published
2000-08-15
Pages
2060-71
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC316859
Subset
IM
Grants
NCI NIH HHS · R37 CA050239 · United States
NCI NIH HHS · 5T32CA09361-19 · United States
NCI NIH HHS · R01 CA050239 · United States
NCI NIH HHS · T32 CA009361 · United States
NCI NIH HHS · CA50239 · United States
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PubMed source PMC Full Text View journal details
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