2. Academic Validation
  3. The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site

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

  • Mol Cell. 2006 Dec 8;24(5):677-688. doi: 10.1016/j.molcel.2006.10.014.
Tudor Moldoveanu 1,  Qian Liu 2,  Ante Tocilj 2,  Mark Watson 3,  Gordon Shore 4,  Kalle Gehring 5
Affiliations

Affiliations

  • 1 Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, Canada H3G 1Y6. Electronic address: [email protected].
  • 2 Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, Canada H3G 1Y6.
  • 3 GeminX Biotechnologies, Inc., Place du Parc, Montreal, QC, Canada H2X 4A5.
  • 4 Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, Canada H3G 1Y6; GeminX Biotechnologies, Inc., Place du Parc, Montreal, QC, Canada H2X 4A5.
  • 5 Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, Canada H3G 1Y6. Electronic address: [email protected].
PMID: 17157251 DOI: 10.1016/j.molcel.2006.10.014
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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