The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site - PubMed (original) (raw)

Comparative Study

. 2006 Dec 8;24(5):677-688.

doi: 10.1016/j.molcel.2006.10.014.

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Comparative Study

The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site

Tudor Moldoveanu et al. Mol Cell. 2006.

Free article

Abstract

BAK/BAX-mediated mitochondrial outer-membrane permeabilization (MOMP) drives cell death during development and tissue homeostasis from zebrafish to humans. In most cancers, this pathway is inhibited by BCL-2 family antiapoptotic members, which bind and block the action of proapoptotic BCL proteins. We report the 1.5 A crystal structure of calpain-proteolysed BAK, cBAK, to reveal a zinc binding site that regulates its activity via homodimerization. cBAK contains an occluded BH3 peptide binding pocket that binds a BID BH3 peptide only weakly . Nonetheless, cBAK requires activation by truncated BID to induce cytochrome c release in mitochondria isolated from bak/bax double-knockout mouse embryonic fibroblasts. The BAK-mediated MOMP is inhibited by low micromolar zinc levels. This inhibition is alleviated by mutation of the zinc-coordination site in BAK. Our results link directly the antiapoptotic effects of zinc to BAK.

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