Research Publications

Back

The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity


Hinds, MG; Lackmann, M; Skea, GL; Harrison, PJ; Huang, DCS; Day, CL
2003-04-01
EMBO JOURNAL
Journal Article
22
7
1497-1507
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. Therefore, pro-survival Bcl-2-like molecules probably control the activation of downstream effectors by a mechanism that remains to be elucidated.
OXFORD UNIV PRESS
ANTIAPOPTOTIC PROTEIN BCL-2; NMR STRUCTURE CALCULATION; CELL-DEATH; ENDOPLASMIC-RETICULUM; BH3-ONLY PROTEINS; NUCLEAR-ENVELOPE; PEPTIDE COMPLEX; FAMILY MEMBERS; X-L; APOPTOSIS
10.1093/emboj/cdg144
Refer to copyright notice on published article.

Back
Creation Date 2003-04-01 12:00:00