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| Subject Categories: Structural Biology | Differentiation & Death |
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| The EMBO Journal
(2003) 22, 1497–1507, doi:10.1093/emboj/cdg144 |
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| The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity |
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| Mark G. Hinds1, Martin Lackmann2, Gretchen L. Skea3, Penny J. Harrison3, David C. S. Huang1 and Catherine L. Day3 |
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1 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia 2 Ludwig Institute for Cancer Research, Melbourne, Victoria 3050, Australia 3 Department of Biochemistry, University of Otago, Dunedin 9001, New Zealand To whom correspondence should be addressed Catherine L. Day, catherine.day@stonebow.otago.ac.nz Received 14 November 2002; Revised 21 January 2003; Accepted 4 February 2003. |
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| Abstract |
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| 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-xL 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-xL. 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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| Keywords: apoptosis, Bcl-2, binding, NMR, protein structure |
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