| First Author | Gautier F | Year | 2011 |
| Journal | Mol Cell Biol | Volume | 31 |
| Issue | 4 | Pages | 832-44 |
| PubMed ID | 21173168 | Mgi Jnum | J:170379 |
| Mgi Id | MGI:4946425 | Doi | 10.1128/MCB.00161-10 |
| Citation | Gautier F, et al. (2011) Bax activation by engagement with, then release from, the BH3 binding site of Bcl-xL. Mol Cell Biol 31(4):832-44 |
| abstractText | Bcl-2 homologues (such as Bcl-x(L)) promote survival in part through sequestration of 'activator' BH3-only proteins (such as Puma), preventing them from directly activating Bax. It is thus assumed that inhibition of interactions between activators and Bcl-x(L) is a prerequisite for small molecules to antagonize Bcl-x(L) and induce cell death. The biological properties, described here of a terphenyl-based alpha-helical peptidomimetic inhibitor of Bcl-x(L) attest that displacement of Bax from Bcl-x(L) is also critical. Terphenyl 14 triggers Bax-dependent but Puma-independent cell death, disrupting Bax/Bcl-x(L) interactions without affecting Puma/Bcl-x(L) interactions. In cell-free assays, binding of inactive Bax to Bcl-x(L), followed by its displacement from Bcl-x(L) by terphenyl 14, produces mitochondrially permeabilizing Bax molecules. Moreover, the peptidomimetic kills yeast cells that express Bax and Bcl-x(L), and it uses Bax-binding Bcl-x(L) to induce mammalian cell death. Likewise, ectopic expression of Bax in yeast and mammalian cells enhances sensitivity to another Bcl-x(L) inhibitor, ABT-737, when Bcl-x(L) is present. Thus, the interaction of Bcl-x(L) with Bax paradoxically primes Bax at the same time it keeps Bax activity in check, and displacement of Bax from Bcl-x(L) triggers an apoptotic signal by itself. This mechanism might contribute to the clinical efficiency of Bcl-x(L) inhibitors. |
