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 α helices, although b...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-04, Vol.275 (15), p.11092-11099
Main Authors: Zhang, Hong, Cowan-Jacob, Sandra W., Simonen, Marjo, Greenhalf, William, Heim, Jutta, Meyhack, Bernd
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Apoptosis
Base Sequence
bcl-2-Associated X Protein
Binding Sites
Cell Death
Cell Line
Humans
Minor Histocompatibility Antigens
Models, Molecular
Molecular Sequence Data
Proteins - chemistry
Proteins - physiology
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-bcl-2
Rats
Saccharomyces cerevisiae - physiology
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Summary: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 α 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.275.15.11092