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The structure of Bcl‐w reveals a role for the C‐terminal residues in modulating biological activity
Author(s) -
Hinds Mark G.,
Lackmann Martin,
Skea Gretchen L.,
Harrison Penny J.,
Huang David C. S.,
Day Catherine L.
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg144
Subject(s) - biology , effector , microbiology and biotechnology , plasma protein binding , biophysics , binding site , groove (engineering) , terminal (telecommunication) , dna binding protein , biochemistry , transcription factor , telecommunications , materials science , computer science , metallurgy , gene
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.