Structural basis of BFL-1 for its interaction with BAX and its anti-apoptotic action in mammalian and yeast cells.

BFL-1 is the smallest member of the BCL-2 family and has been shown to retard apoptosis in various cell lines. However, the structural basis for its function remains unclear. Molecular modeling showed that BFL-1 could have a similar core structure as BCL-xL, consisting of seven alpha helices, although both proteins ...
share only the conserved BCL-2 homology domains (BH1 and BH2 domains), but otherwise have very limited sequence homology, particularly in the N-terminal region. We demonstrated in the yeast two-hybrid system that BFL-1 interacts strongly with human BAX but is not able to form homodimers nor to interact with human BCL-2 or BCL-xL. Overexpression experiments in REF52 rat fibroblasts showed that BFL-1 conferred increased resistance to apoptosis induced by serum deprivation. BFL-1 had also the ability to neutralize BAX lethality in yeast. BAX requires the BH3 domain for interaction with BFL-1. However, the minimal region of BFL-1 for the interaction with BAX in coimmunoprecipitation experiments was not sufficient to protect cells from apoptosis. Further examination of BFL-1 and several other anti-apoptotic proteins suggests a more general type of structure based on structural motifs, i.e. a hydrophobic pocket for the binding of proapoptotic proteins, rather than extended sequence homologies.
Mesh Terms:
Amino Acid Sequence, Animals, Apoptosis, Base Sequence, Binding Sites, Cell Death, Cell Line, Humans, Models, Molecular, Molecular Sequence Data, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Rats, Saccharomyces cerevisiae, bcl-2-Associated X Protein
J. Biol. Chem.
Date: Apr. 14, 2000
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