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

نویسندگان

  • M C Wei
  • T Lindsten
  • V K Mootha
  • S Weiler
  • A Gross
  • M Ashiya
  • C B Thompson
  • S J Korsmeyer
چکیده

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.

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عنوان ژورنال:
  • Genes & development

دوره 14 16  شماره 

صفحات  -

تاریخ انتشار 2000