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tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c GENES & DEVELOPMENT Wei, M. C., LINDSTEN, T., Mootha, V. K., Weiler, S., Gross, A., Ashiya, M., Thompson, C. B., Korsmeyer, S. J. 2000; 14 (16): 2060-2071

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.

View details for Web of Science ID 000088871600008

View details for PubMedID 10950869