tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c
- Michael C. Wei1,2,
- Tullia Lindsten4,
- Vamsi K. Mootha1,3,
- Solly Weiler1,
- Atan Gross1,
- Mona Ashiya1,
- Craig B. Thompson4, and
- Stanley J. Korsmeyer1,5
- 1Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Boston, Massachusetts 02115 USA; 2Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri 63110 USA; 3Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115 USA; 4Abramson Family Cancer Research Institute and Departments of Medicine, and Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 USA
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 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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Footnotes
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↵5 Corresponding author.
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E-MAIL stanley_korsmeyer{at}dfci.harvard.edu; FAX (617) 632-6401.
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- Received May 10, 2000.
- Accepted June 28, 2000.
- Cold Spring Harbor Laboratory Press
