tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c
MC Wei, T Lindsten, VK Mootha, S Weiler… - Genes & …, 2000 - genesdev.cshlp.org
MC Wei, T Lindsten, VK Mootha, S Weiler, A Gross, M Ashiya, CB Thompson, SJ Korsmeyer
Genes & development, 2000•genesdev.cshlp.orgTNFR1/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 α-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 …
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 α-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 …
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 α-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.
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