Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function
- Author(s)
- Chen, L; Willis, SN; Wei, A; Smith, BJ; Fletcher, JI; Hinds, MG; Colman, PM; Day, CL; Adams, JM; Huang, DCS;
- Details
- Publication Year 2005-02-04,Volume 17,Issue #3,Page 393-403
- Journal Title
- MOLECULAR CELL
- Publication Type
- Journal Article
- Abstract
- Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-x(L), and Bcl-w but only weakly to A1 and not to Mcl-1. Strikingly, Noxa bound only Mcl-1 and A1. In accord with their complementary binding, Bad and Noxa cooperated to induce potent killing. The results suggest that apoptosis relies on selective interactions between particular subsets of these proteins and that it should be feasible to discover BH3-mimetic drugs that inactivate specific prosurvival targets.
- Publisher
- CELL PRESS
- Keywords
- CELL-DEATH; CYTOCHROME-C; SURVIVAL FACTOR; FAMILY; COMPLEX; MITOCHONDRIA; MEMBER; BIM; PEPTIDE; RELEASE
- Publisher's Version
- https://doi.org/10.1016/j.molcel.2004.12.030
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2005-02-04 12:00:00