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

Tudor Moldoveanu1, Qian Liu1, Ante Tocilj1

  • 1Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, QC, Canada H3G 1Y6.

Molecular Cell
|December 13, 2006
PubMed

Insights

Zinc inhibits the cell death protein BAK by binding to a newly discovered site, a finding that links zinc

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • Mitochondrial outer-membrane permeabilization (MOMP) is crucial for cell death, regulated by BCL-2 family proteins.
  • Cancer cells often evade apoptosis by inhibiting proapoptotic proteins like BAK and BAX.

Purpose of the Study:

  • To elucidate the structural and functional role of zinc in regulating BAK-mediated MOMP.
  • To understand the mechanism by which zinc exerts its antiapoptotic effects.

Main Methods:

  • 1.5 A crystal structure determination of calpain-proteolysed BAK (cBAK).
  • Biochemical assays using isolated mitochondria from bak/bax double-knockout mouse embryonic fibroblasts.
  • Site-directed mutagenesis of the identified zinc-coordination site in BAK.

Main Results:

  • A novel zinc binding site on cBAK was identified, regulating its homodimerization and activity.
  • cBAK exhibits weak binding to BID BH3 peptide but requires truncated BID for cytochrome c release.
  • Low micromolar zinc levels inhibit BAK-mediated MOMP, an effect reversed by mutating the zinc-binding site.

Conclusions:

  • Zinc directly links to the antiapoptotic function of BAK by inhibiting its activity through a specific binding site.
  • This discovery provides a molecular basis for zinc's role in cellular survival and potentially cancer biology.

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