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

Author(s): Lee, EF; Dewson, G; Evangelista, M; Pettikiriarachchi, A; Zhu, H; Colman, PM; Fairlie, WD;
Details: Publication Year 2014-11-03,Volume 289,Issue #52,Page 36001-36017
Journal Title: Journal of Biological Chemistry
Publication Type: Journal Article
Abstract: 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.
Publisher: ASBMB
Keywords: apoptosis ; B-cell lymphoma 2 Bcl-2 family ; cell death ; peptides; protein structure
Research Division(s): Structural Biology; Cell Signalling And Cell Death
Link To PubMed Central Version: http://www.jbc.org/
Publisher's Version: https://doi.org/10.1074/jbc.M114.610758
NHMRC Grants: NHMRC/1016701, NHMRC/1041936, NHMRC/1008329, NHMRC/1024620, NHMRC/1022618,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2014-11-14 01:51:47

Last Modified: 2015-01-22 01:55:39