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Molecular and Cellular Biology, March 2000, p. 1604-1615, Vol. 20, No. 5
The Burnham Institute, La Jolla, California
92037
Received 13 September 1999/Returned for modification 21 October
1999/Accepted 29 November 1999
Bax is a proapoptotic member of the Bcl-2 family of proteins which
localizes to and uses mitochondria as its major site of action. Bax
normally resides in the cytoplasm and translocates to mitochondria in
response to apoptotic stimuli, and it promotes apoptosis in two ways:
(i) by disrupting mitochondrial membrane barrier function by formation
of ion-permeable pores in mitochondrial membranes and (ii) by binding
to antiapoptotic Bcl-2 family proteins via its BH3 domain and
inhibiting their functions. A hairpin pair of amphipathic
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Copyright © 2000, American Society for Microbiology. All rights reserved.
The Putative Pore-Forming Domain of Bax Regulates
Mitochondrial Localization and Interaction with
Bcl-XL

-helices
(
5-
6) in Bax has been predicted to participate in membrane
insertion and pore formation by Bax. We mutagenized several charged
residues in the
5-
6 domain of Bax, changing them to alanine.
These substitution mutants of Bax constitutively localized to
mitochondria and displayed a gain-of-function phenotype when expressed
in mammalian cells. Furthermore, substitution of 8 out of 10 charged
residues in the
5-
6 domain of Bax resulted in a loss of
cytotoxicity in yeast but a gain-of-function phenotype in mammalian
cells. The enhanced function of this Bax mutant was correlated with
increased binding to Bcl-XL, through a BH3-independent mechanism. These observations reveal new functions for the
5-
6 hairpin loop of Bax: (i) regulation of mitochondrial targeting and (ii)
modulation of binding to antiapoptotic Bcl-2 proteins.
*
Corresponding author. Mailing address: The Burnham
Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 646-3140. Fax: (858) 646-3194. E-mail: jreed{at}burnham-inst.org.
Present address: Institut Pasteur, URA 1773 CNRS, 75724 Paris Cedex
15, France.
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