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(Received for publication, July 10, 1997)
From IDUN Pharmaceuticals Inc., La Jolla, California 92037
Bad, an inducer of programmed cell death, was
recently isolated from a mouse cDNA library by its ability to bind
to the anti-apoptotic protein BCL-2. Sequence analysis suggested that
Bad was a member of the BCL-2 gene family that encodes both
inducers and inhibitors of programmed cell death. To further analyze
the role of BAD in the network of homo- and heterodimers formed by the
BCL-2 family, we have cloned the human homologue of BAD and
assessed its biological activity and its interactions with wild type
and mutant BCL-2 family proteins. Our results indicate that the human
BAD protein, like its mouse homologue, is able to induce apoptosis when
transfected into mammalian cells. Furthermore, in yeast two-hybrid
assays as well as quantitative in vitro interaction assays,
human Bad interacted with BCL-2 and BCL-XL. Sequence
alignments of human BAD revealed the presence of a BH-3 homology domain
as seen in other BCL-2 family proteins. Peptides derived from this
domain were able to completely inhibit the dimerization of BAD with
BCL-XL. Thus, as previously shown for BAX, BAK, BCL-2, and
BCL-XL, the BH3 domain of BAD is required for its
dimerization with other BCL-2 family proteins. BAD was further analyzed
for its ability to bind to various mutants of BCL-2 and
BCL-XL that have lost the ability to bind BAX and BAK, some
of which retain biological activity and some of which do not.
Surprisingly, all of the mutated BCL-2 and BCL-XL proteins
analyzed strongly interacted with human BAD. Our data thus indicate
that mutations in BCL-2 and BCL-XL can differentially
affect the heterodimeric binding of different death-promoting proteins
and have implications concerning the relationship between
heterodimerization and biological activity.
Volume 272, Number 49,
Issue of December 5, 1997
pp. 30866-30872
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Dimerization Properties of Human BAD
IDENTIFICATION OF A BH-3 DOMAIN AND ANALYSIS OF ITS BINDING TO
MUTANT BCL-2 AND BCL-XL PROTEINS
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