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

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 a...

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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
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container_issue 7
container_start_page 1497
container_title The EMBO journal
container_volume 22
creator Hinds, Mark G.
Lackmann, Martin
Skea, Gretchen L.
Harrison, Penny J.
Huang, David C. S.
Day, Catherine L.
description 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.
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identifier ISSN: 0261-4189
ispartof The EMBO journal, 2003-04, Vol.22 (7), p.1497-1507
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1460-2075
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_152889
source PubMed Central(OpenAccess)
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
title The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity
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