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.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / drug effects
  • Binding Sites
  • Calpain / metabolism
  • Chlorides / pharmacology*
  • Crystallography, X-Ray
  • Humans
  • KB Cells
  • Magnetic Resonance Spectroscopy
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / metabolism
  • Protein Conformation
  • Protein Structure, Secondary
  • Proto-Oncogene Proteins / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Sensitivity and Specificity
  • Zinc Compounds / pharmacology*
  • bcl-2 Homologous Antagonist-Killer Protein / antagonists & inhibitors*
  • bcl-2 Homologous Antagonist-Killer Protein / chemistry*
  • bcl-2 Homologous Antagonist-Killer Protein / genetics


  • BAK1 protein, human
  • Bax protein (53-86)
  • Chlorides
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Zinc Compounds
  • bcl-2 Homologous Antagonist-Killer Protein
  • zinc chloride
  • Calpain