Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain Bax
- Author(s)
- Fletchera, JI; Meusburger, S; Hawkins, CJ; Riglar, DT; Lee, EF; Fairlie, WD; Huang, DCS; Adams, JM;
- Details
- Publication Year 2008-11-25,Volume 105,Issue #47,Page 18081-18087
- Journal Title
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- Publication Type
- Journal Article
- Abstract
- A central issue in the control of apoptosis is whether its essential mediators Bax and Bak must be restrained by Bcl-2-like prosurvival relatives to prevent their damaging mitochondria and unleashing apoptosis. The issue is particularly vexed for Bax, which is largely a cytosolic monomer in unstressed cells. To determine whether Bax regulation requires its binding by prosurvival relatives, we replaced a conserved aspartate in its BH3 interaction domain with arginine. Bax D68R functioned and behaved like wild-type Bax in localization and activation but had greatly impaired binding to the prosurvival family members. Nevertheless, Bcl-x(L) remained able to block apoptosis induced by Bax D68R. Whereas cells with sufficient Bcl-x(L) tolerated expression of Bax D68R, it provoked apoptosis when Bcl-x(L) was absent, downregulated, or inactivated. Moreover, Bax D68R rendered membrane bound by a C-terminal anchor mutation overwhelmed endogenous Bcl-x(L) and killed cells. These unexpected results suggest that engagement of Bax by its prosurvival relatives is a major barrier to its full activation. We propose that the Bcl-2-like proteins must capture the small proportion of Bax molecules with an exposed BH3 domain, probably on the mitochondrial membrane, to prevent Bax-imposed cell death, but that Bcl-x(L) also controls Bax by other mechanisms.
- Publisher
- NATL ACAD SCIENCES
- Keywords
- CELL-DEATH; BH3-ONLY PROTEINS; PROAPOPTOTIC FUNCTION; BH3 DOMAINS; FAMILY; BCL-X(L); ACTIVATION; INHIBITOR; DISTINCT; BIM
- Publisher's Version
- https://doi.org/10.1073/pnas.0808691105
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2008-11-25 12:00:00