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  • The EMBO Journal (2003) 22, 1497 - 1507
  • doi:10.1093/emboj/cdg144

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

Mark G. Hinds1, Martin Lackmann2, Gretchen L. Skea3, Penny J. Harrison3, David C. S. Huang1 and Catherine L. Day3

  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

Correspondence to:

Catherine L. Day, E-mail: catherine.day@stonebow.otago.ac.nz

Received 14 November 2002; Accepted 4 February 2003; Revised 21 January 2003

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.

  • Keywords:

    • apoptosis,
    • Bcl-2,
    • binding,
    • NMR,
    • protein structure