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

Mol Cell. 2005 Feb 18;17(4):525-35. doi: 10.1016/j.molcel.2005.02.003.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • BH3 Interacting Domain Death Agonist Protein
  • Bcl-2-Like Protein 11
  • Carrier Proteins / metabolism
  • Cytochromes c / metabolism
  • HeLa Cells
  • Humans
  • Intracellular Membranes / metabolism*
  • Membrane Proteins / metabolism
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism
  • Molecular Sequence Data
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism
  • Peptide Fragments / metabolism*
  • Permeability
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / chemistry
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Sequence Homology, Amino Acid
  • bcl-2-Associated X Protein
  • bcl-X Protein

Substances

  • Apoptosis Regulatory Proteins
  • BAX protein, human
  • BCL2L1 protein, human
  • BCL2L11 protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Bax protein (53-86)
  • Bcl-2-Like Protein 11
  • Carrier Proteins
  • Membrane Proteins
  • Mitochondrial Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Cytochromes c