Bax Crystal Structures Reveal How BH3 Domains Activate Bax and Nucleate Its Oligomerization to Induce Apoptosis
- Author(s)
- Czabotar, PE; Westphal, D; Dewson, G; Ma, S; Hockings, C; Fairlie, WD; Lee, EF; Yao, SG; Robin, AY; Smith, BJ; Huang, DCS; Kluck, RM; Adams, JM; Colman, PM;
- Details
- Publication Year 2013-01-31,Volume 152,Issue #3,Page 519-531
- Journal Title
- CELL
- Publication Type
- Journal Article
- Abstract
- In stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to mediate this pivotal, poorly understood step. To clarify the conformational changes that induce Bax oligomerization, we determined crystal structures of Bax Delta C21 treated with detergents and BH3 peptides. The peptides bound the Bax canonical surface groove but, unlike their complexes with prosurvival relatives, dissociated Bax into two domains. The structures define the sequence signature of activator BH3 domains and reveal how they can activate Bax via its groove by favoring release of its BH3 domain. Furthermore, Bax helices alpha 2-alpha 5 alone adopted a symmetric homodimer structure, supporting the proposal that two Bax molecules insert their BH3 domain into each other's surface groove to nucleate oligomerization. A planar lipophilic surface on this homodimer may engage the membrane. Our results thus define critical Bax transitions toward apoptosis.
- Publisher
- CELL PRESS
- Keywords
- BCL-2 PROTEIN FAMILY; MEMBRANE PERMEABILIZATION; PROAPOPTOTIC BAX; CELL-DEATH; MITOCHONDRIAL APOPTOSIS; PORE FORMATION; X-RAY; DIMERIZATION; MECHANISM; BCL-X(L)
- Research Division(s)
- Structural Biology; Molecular Genetics Of Cancer; Cell Signalling And Cell Death; Chemical Biology
- Publisher's Version
- https://doi.org/10.1016/j.cell.2012.12.031
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Creation Date: 2013-01-31 12:00:00
Last Modified: 2015-06-19 02:17:51