| Literature DB >> 17157251 |
Tudor Moldoveanu1, Qian Liu2, Ante Tocilj2, Mark Watson3, Gordon Shore4, Kalle Gehring5.
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.Entities:
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Year: 2006 PMID： 17157251 DOI： 10.1016/j.molcel.2006.10.014
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970