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Molecular and Cellular Biology, March 2000, p. 1604-1615, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Putative Pore-Forming Domain of Bax Regulates Mitochondrial Localization and Interaction with Bcl-XL

Shahrzad Nouraini, Emmanuelle Six,dagger Shigemi Matsuyama, Stainslaw Krajewski, and John C. Reed*

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 alpha -helices (alpha 5-alpha 6) in Bax has been predicted to participate in membrane insertion and pore formation by Bax. We mutagenized several charged residues in the alpha 5-alpha 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 alpha 5-alpha 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 alpha 5-alpha 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.

dagger Present address: Institut Pasteur, URA 1773 CNRS, 75724 Paris Cedex 15, France.

Molecular and Cellular Biology, March 2000, p. 1604-1615, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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