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J Biol Chem, Vol. 274, Issue 25, 17941-17945, June 18, 1999
From the Center for Apoptosis Research and the Department of
Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson
University, Philadelphia, Pennsylvania 19107
To elucidate the mechanism of activation of
procaspase-9 by Apaf-1, we produced recombinant full-length Apaf-1 and
purified it to complete homogeneity. Here we show using gel filtration that full-length Apaf-1 exists as a monomer that can be transformed to
an oligomeric complex made of at least eight subunits after binding to
cytochrome c and dATP. Apaf-1 binds to cytochrome
c in the absence of dATP but does not form the oligomeric
complex. However, when dATP is added to the cytochrome
c-bound Apaf-1 complex, complete oligomerization occurs,
suggesting that oligomerization is driven by hydrolysis of dATP. This
was supported by the observation that ATP, but not the nonhydrolyzable
adenosine 5'-O-(thiotriphosphate), can induce
oligomerization of the Apaf-1-cytochrome c complex. Like
the spontaneously oligomerizing Apaf-530, which lacks its WD-40 domain,
the oligomeric full-length Apaf-1-cytochrome c complex can
bind and process procaspase-9 in the absence of additional dATP or
cytochrome c. However, unlike the truncated Apaf-530
complex, the full-length Apaf-1 complex can release the mature
caspase-9 after processing. Once released, mature caspase-9 can process procaspase-3, setting into motion the caspase cascade. These
observations indicate that cytochrome c and dATP are
required for oligomerization of Apaf-1 and suggest that the WD-40
domain plays an important role in oligomerization of full-length Apaf-1
and the release of mature caspase-9 from the Apaf-1 oligomeric complex.
Cytochrome c and dATP-mediated Oligomerization of
Apaf-1 Is a Prerequisite for Procaspase-9 Activation
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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