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A stapled BID BH3 helix directly binds and activates BAX.

Molecular cell | Oct 20, 2006

http://www.ncbi.nlm.nih.gov/pubmed/17052454

BAX is a multidomain proapoptotic BCL-2 family protein that resides in the cytosol until activated by an incompletely understood trigger mechanism, which facilitates BAX translocation to mitochondria and downstream death events. Whether BAX is activated by direct contact with select BH3-only members of the BCL-2 family is highly debated. Here we detect and quantify a direct binding interaction between BAX and a hydrocarbon-stapled BID BH3 domain, which triggers the functional activation of BAX at nanomolar doses in vitro. Chemical reinforcement of BID BH3 alpha helicity was required to reveal the direct BID BH3-BAX association. We confirm the specificity of this BH3 interaction by characterizing a stapled BAD BH3 peptide that interacts with antiapoptotic BCL-X(L) but does not bind or activate BAX. We further demonstrate that membrane targeting of stapled BID BH3 optimizes its ability to activate BAX, supporting a model in which BID directly engages BAX to trigger mitochondrial apoptosis.

Pubmed ID: 17052454 RIS Download

Mesh terms: Amino Acid Sequence | Apoptosis | BH3 Interacting Domain Death Agonist Protein | Cell Membrane | Dose-Response Relationship, Drug | Humans | Jurkat Cells | Liposomes | Molecular Sequence Data | Peptides | Protein Binding | Protein Transport | Sequence Homology, Amino Acid | bcl-2-Associated X Protein | bcl-X Protein

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Associated grants

  • Agency: NCI NIH HHS, Id: 5P01CA92625
  • Agency: NCI NIH HHS, Id: 5R37CA050239
  • Agency: NHLBI NIH HHS, Id: K08 HL074049
  • Agency: NHLBI NIH HHS, Id: K08HL074049

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