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 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.
Wei
M C
MC
Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
Lindsten
T
T
Mootha
V K
VK
Weiler
S
S
Gross
A
A
Ashiya
M
M
Thompson
C B
CB
Korsmeyer
S J
SJ
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
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