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

TNER1/Eas engagement results in the cleavage of cytosolic BID to truncated tBID, which translocates to mitochondria. Immunodepletion and gene disrupti on indicate BID is required for cytochrome c release. Surprisingly, the thr ee-dimensional structure of this BH3 domain-only molecule revealed two hydr ophobic alpha-helices suggesting tBID itself might be a pore-forming protei n. 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 i n an allosteric activation of BAK, inducing its intramembranous oligomeriza tion into a proposed pore for cytochrome c efflux, integrating the pathway from death receptors to cell demise.