The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity.
Article Details
- CitationCopy to clipboard
Hinds MG, Lackmann M, Skea GL, Harrison PJ, Huang DC, Day CL
The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity.
EMBO J. 2003 Apr 1;22(7):1497-507.
- PubMed ID
- 12660157 [ View in PubMed]
- Abstract
Pro-survival Bcl-2-related proteins, critical regulators of apoptosis, contain a hydrophobic groove targeted for binding by the BH3 domain of the pro-apoptotic BH3-only proteins. The solution structure of the pro-survival protein Bcl-w, presented here, reveals that the binding groove is not freely accessible as predicted by previous structures of pro-survival Bcl-2-like molecules. Unexpectedly, the groove appears to be occluded by the C-terminal residues. Binding and kinetic data suggest that the C-terminal residues of Bcl-w and Bcl-x(L) modulate pro-survival activity by regulating ligand access to the groove. Binding of the BH3-only proteins, critical for cell death initiation, is likely to displace the hydrophobic C-terminal region of Bcl-w and Bcl-x(L). Moreover, Bcl-w does not act only by sequestering the BH3-only proteins. There fore, pro-survival Bcl-2-like molecules probably control the activation of downstream effectors by a mechanism that remains to be elucidated.