The functional differences of pro-survival and pro-apoptotic B cell lymphoma 2 (Bcl-2) proteins depend on structural differences in their Bcl-2 Homology 3 (BH3) domains
- Lee, EF; Dewson, G; Evangelista, M; Pettikiriarachchi, A; Zhu, H; Colman, PM; Fairlie, WD;
Publication Year 2014-11-03, Volume 289, Issue #52, Page 36001-36017
- Journal Title
- Journal of Biological Chemistry
- Publication Type
- Journal Article
- Bcl-2 Homology 3 (BH3) domains are short sequence motifs that mediate nearly all protein-protein interactions between B cell lymphoma 2 (Bcl-2) family proteins in the intrinsic apoptotic cell death pathway. These sequences are found on both pro-survival and pro-apoptotic members even though their primary function is believed to be associated with induction of cell death. Here, we identify critical features of the BH3 domains of pro-survival proteins that distinguish them functionally from their pro-apoptotic counterparts. Biochemical and X-ray crystallographic studies demonstrate that these differences reduce the capacity of most pro-survival proteins to form high affinity "BH3-in-groove" complexes that are critical for cell death induction. Switching these residues for the corresponding residues in Bcl-2 homologous antagonist/killer (Bak) increases the binding affinity of isolated BH3 domains to pro-survival proteins, however, their exchange in the context of the parental protein causes rapid proteasomal degradation due to protein destabilization. This is supported by further X-ray crystallographic studies that capture elements of this destabilization in one pro-survival protein, Bcl-w. In pro-apoptotic Bak, we demonstrate that the corresponding distinguishing residues are important for its stability, cell-killing capacity, and antagonism by pro-survival proteins.
- apoptosis ; B-cell lymphoma 2 Bcl-2 family ; cell death ; peptides; protein structure
- WEHI Research Division(s)
- Structural Biology; Cell Signalling And Cell Death
- Link To PubMed Central Version
- Publisher's Version
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- Refer to copyright notice on published article.
Creation Date: 2014-11-14 01:51:47Last Modified: 2015-01-22 01:55:39