Proapoptotic BH3-only proteins trigger membrane integration of prosurvival Bcl-w and neutralize its activity
- Author(s)
- Wilson-Annan, J; O'Reilly, LA; Crawford, SA; Hausmann, G; Beaumont, JG; Parma, LP; Chen, L; Lackmann, M; Lithgow, T; Hinds, MG; Day, CL; Adams, JM; Huang, DCS;
- Details
- Publication Year 2003-09-01,Volume 162,Issue #5,Page 877-887
- Journal Title
- JOURNAL OF CELL BIOLOGY
- Publication Type
- Journal Article
- Abstract
- Prosurvival Bcl-2-like proteins, like Bcl-w, are thought to function on organelles such as the mitochondrion and to be targeted to them by their hydrophobic COOH-terminal domain. We unexpectedly found, however, that the membrane association of Bcl-w was enhanced during apoptosis. In healthy cells, Bcl-w was loosely attached to the mitochondrial membrane, but it was converted into an integral membrane protein by cytotoxic signals that induce binding of BH3-only proteins, such as Bim, or by the addition of BH3 peptides to lysates. As the structure of Bcl-w has revealed that its COOH-terminal domain occupies the hydrophobic groove where BH3 ligands bind, displacement of that domain by a BH3 ligand would displace the hydrophobic COOH-terminal residues, allowing their insertion into the membrane. To determine whether BH3 ligation is sufficient to induce the enhanced membrane affinity, or to render Bcl-w proapoptotic, we mimicked their complex by tethering the Bim BH3 domain to the NH2 terminus of Bcl-w. The chimera indeed bound avidly to membranes, in a fashion requiring the COOH-terminal domain, but neither promoted nor inhibited apoptosis. These results suggest that ligation of a proapoptotic BH3-only protein alters the conformation of Bcl-w, enhances membrane association, and neutralizes its survival function.
- Publisher
- ROCKEFELLER UNIV PRESS
- Keywords
- OUTER MITOCHONDRIAL-MEMBRANES; CELL-CYCLE ENTRY; OR-DEATH SWITCH; FAMILY-MEMBERS; ENDOPLASMIC-RETICULUM; LYMPHOCYTE APOPTOSIS; NUCLEAR-ENVELOPE; BINDING PROTEINS; X-L; BAX
- Publisher's Version
- https://doi.org/10.1083/job.200302144
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2003-09-01 12:00:00