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

• Published in: The EMBO journal 2003-04, Vol.22 (7), p.1497-1507
• Main Authors: Hinds, Mark G., Lackmann, Martin, Skea, Gretchen L., Harrison, Penny J., Huang, David C. S., Day, Catherine L.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; apoptosis; Apoptosis Regulatory Proteins; Bcl-2; bcl-X Protein; binding; EMBO07; EMBO40; Humans; Models, Molecular; Molecular Sequence Data; NMR; Protein Conformation; protein structure; Proteins; Proteins - chemistry; Proteins - physiology; Proto-Oncogene Proteins c-bcl-2 - chemistry; Proto-Oncogene Proteins c-bcl-2 - metabolism; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - metabolism; Sequence Homology, Amino Acid; Survival
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/cdg144

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.