BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly.

Using a Bax-dependent membrane-permeabilization assay, we show that peptides corresponding to the BH3 domains of Bcl-2 family "BH3-only" proteins have dual functions. Several BH3 peptides relieved the inhibition of Bax caused by the antiapoptotic Bcl-x(L) and/or Mcl-1 proteins, some displaying a specificity for either Bcl-x(L) or Mcl-1. Besides having this ...
derepression function, the Bid and Bim peptides activated Bax directly and were the only BH3 peptides tested that could potently induce cytochrome c release from mitochondria in cultured cells. Furthermore, Bax activator molecules (cleaved Bid protein and the Bim BH3 peptide) synergistically induced cytochrome c release when introduced into cells along with derepressor BH3 peptides. These observations support a unified model of BH3 domain function, encompassing both positive and negative regulation of other Bcl-2 family members. In this model, the simple inhibition of antiapoptotic functions is insufficient to induce apoptosis unless a direct activator of Bax or Bak is present.
Mesh Terms:
Amino Acid Sequence, Apoptosis, Apoptosis Regulatory Proteins, BH3 Interacting Domain Death Agonist Protein, Carrier Proteins, Cytochromes c, HeLa Cells, Humans, Intracellular Membranes, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Molecular Sequence Data, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins, Peptide Fragments, Permeability, Protein Structure, Tertiary, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Sequence Homology, Amino Acid, bcl-2-Associated X Protein, bcl-X Protein
Mol. Cell
Date: Feb. 18, 2005
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