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Science 25 July 2003:
Vol. 301. no. 5632, pp. 513 - 517
DOI: 10.1126/science.1083995
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Reports

VDAC2 Inhibits BAK Activation and Mitochondrial Apoptosis

Emily H.-Y. Cheng,1 Tatiana V. Sheiko,2 Jill K. Fisher,1 William J. Craigen,2 Stanley J. Korsmeyer1*

The multidomain proapoptotic molecules BAK or BAX are required to initiate the mitochondrial pathway of apoptosis. How cells maintain the potentially lethal proapoptotic effector BAK in a monomeric inactive conformation at mitochondria is unknown. In viable cells, we found BAK complexed with mitochondrial outer-membrane protein VDAC2, a VDAC isoform present in low abundance that interacts specifically with the inactive conformer of BAK. Cells deficient in VDAC2, but not cells lacking the more abundant VDAC1, exhibited enhanced BAK oligomerization and were more susceptible to apoptotic death. Conversely, overexpression of VDAC2 selectively prevented BAK activation and inhibited the mitochondrial apoptotic pathway. Death signals activate "BH3-only" molecules such as tBID, BIM, or BAD, which displace VDAC2 from BAK, enabling homo-oligomerization of BAK and apoptosis. Thus, VDAC2, an isoform restricted to mammals, regulates the activity of BAK and provides a connection between mitochondrial physiology and the core apoptotic pathway.

1 Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030–3498, USA.

* To whom correspondence should be addressed. E-mail: stanley_korsmeyer{at}dfci.harvard.edu

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