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J. Biol. Chem., Vol. 283, Issue 12, 7790-7803, March 21, 2008

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BIM and tBID Are Not Mechanistically Equivalent When Assisting BAX to Permeabilize Bilayer Membranes^*

Oihana Terrones¹, Aitor Etxebarria¹, Ane Landajuela, Olatz Landeta, Bruno Antonsson, and Gorka Basañez²

From the Unidad de Biofísica (Centro Mixto Consejo Superior de Investigaciones Cientificas, Universidad del Pais Vasco/Euskal Herriko Unibertsitatea), Universidad del Pais Vasco/Euskal Herriko Unibertsitatea, P. O. Box 644, 48080 Bilbao, Spain and Merck Serono International S. A., 9 chemin des Mines, 1202 Geneva, Switzerland

BIM and tBID are two BCL-2 homology 3 (BH3)-only proteins with a particularly strong capacity to trigger BAX-driven mitochondrial outer membrane permeabilization, a crucial event in mammalian apoptosis. However, the means whereby BIM and tBID fulfill this task is controversial. Here, we used a reconstituted liposomal system bearing physiological relevance to explore systematically how the BAX-permeabilizing function is influenced by interactions of BIM/BID-derived proteins and BH3 motifs with multidomain BCL-2 family members and with membrane lipids. We found that nanomolar dosing of BIM proteins sufficed to reverse completely the inhibition of BAX permeabilizing activity exerted by all antiapoptotic proteins tested (BCL-2, BCL-X_L, BCL-W, MCL-1, and A1). This effect was reproducible by a peptide representing the BH3 motif of BIM, whereas an equivalent BID BH3 peptide was less potent and more selective, reversing antiapoptotic inhibition. On the other hand, in the absence of BCL-2-type proteins, BIM proteins and the BIM BH3 peptide were inefficient, directly triggering the BAX-permeabilizing function. In contrast, tBID alone potently assisted BAX to permeabilize membranes at least in part by producing a structural distortion in the lipid bilayer via BH3-independent interaction of tBID with cardiolipin. Together, these results support the notion that BIM and tBID follow different strategies to trigger BAX-driven mitochondrial outer membrane permeabilization with strong potency.

Received for publication, October 25, 2007 , and in revised form, January 11, 2008.

^* This work was supported in part by Ministerio de Ciencia y Tecnologia Grant BFU2005-06095. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Figs. 1–6.

¹ Recipients of predoctoral fellowships from the Basque Government.

² To whom correspondence should be addressed: Unidad de Biofísica (CSIC-UPV/EHU), Barrio Sarriena s/n, Leioa 48940, Spain. Tel.: 34-94-6013355; Fax: 34-94-6013360; E-mail: gbzbaasg{at}lg.ehu.es.

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