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

Genes and Development - Tập 14 Số 16 - Trang 2060-2071 - 2000
Michael C. Wei1, Tullia Lindsten2, Vamsi K. Mootha3,1, Solly Weiler1, Atan Gross1, Mona Ashiya1, Boris Turk2, Stanley J. Korsmeyer1
1Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
2Abramson Family Cancer Research Institute and Departments of Medicine, and Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 USA
3Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA

Tóm tắt

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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Tài liệu tham khảo

10.1126/science.281.5381.1322

10.1126/science.277.5324.370

10.1073/pnas.96.10.5492

10.1016/S0092-8674(00)81732-8

10.1016/S0092-8674(00)80572-3

10.1016/S0092-8674(00)81182-4

10.1016/S0092-8674(00)80405-5

10.1126/science.278.5338.687

10.1083/jcb.144.5.891

10.1128/MCB.20.3.929-935.2000

Griffiths, 1999, Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis., J. Cell. Biol., 8, 903, 10.1083/jcb.144.5.903

10.1093/emboj/17.14.3878

10.1101/gad.13.15.1899

10.1074/jbc.274.2.1156

10.1016/S0092-8674(00)81477-4

10.1016/S1097-2765(00)80469-4

Joyner A.L. (1993) Gene targeting : A practical approach. (Oxford University Press, Oxford, UK).

Kelekar, 1997, Bad is a BH3 domain-containing protein that forms an inactivating dimer with Bcl-XL., Mol. Cell. Biol., 17, 7040, 10.1128/MCB.17.12.7040

10.1083/jcb.147.4.809

10.1016/S0092-8674(00)81476-2

10.1016/S0092-8674(00)81590-1

10.1016/S0092-8674(00)80434-1

10.1016/S0092-8674(00)80085-9

10.1016/S0092-8674(00)81589-5

McBride, 1995, Insertion of an uncharged polypeptide into the mitochondrial inner membrane does not require a trans-bilayer electrochemical potential: Effects of positive charges., Biochim. Biophys Acta, 1237, 162, 10.1016/0005-2736(95)00088-K

10.1016/S0092-8674(00)80573-5

10.1038/385353a0

10.1038/381335a0

10.1073/pnas.90.18.8424

Nguyen, 1993, Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence., J. Biol. Chem., 268, 25265, 10.1016/S0021-9258(19)74386-5

10.1038/364806a0

10.1074/jbc.272.49.30866

10.1016/S1097-2765(00)80456-6

10.1038/35019596

10.1126/science.275.5302.983

10.1074/jbc.274.31.21932

10.1073/pnas.94.21.11357

10.1016/0968-0004(88)90219-8

10.1073/pnas.97.2.577

10.1016/S0959-440X(98)80036-5

10.1016/S1097-2765(00)80307-X

10.1101/gad.10.22.2859

10.1016/0955-0674(94)90132-5

10.1083/jcb.139.5.1281

10.1016/0092-8674(95)90411-5

10.1038/23730

10.1016/S0092-8674(00)81733-X

10.1016/S0092-8674(00)81382-3

10.1074/jbc.272.39.24101

10.1016/S0092-8674(00)80501-2

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Genes and Development

Tập 14 Số 16

2060-2071

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