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J. Biol. Chem., Vol. 278, Issue 23, 21124-21128, June 6, 2003

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Solution Structure of Human BCL-w

MODULATION OF LIGAND BINDING BY THE C-TERMINAL HELIX^*

Alexei Yu. Denisov , Murthy S. R. Madiraju , Gang Chen , Abdelkrim Khadir , Pierre Beauparlant , Giorgio Attardo , Gordon C. Shore   and Kalle Gehring  ¶

From the Department of Biochemistry and Montreal Joint Center for Structural Biology, McGill University, Montreal, Quebec H3G 1Y6, Canada and GeminX Biotechnologies Inc., Place du Parc, Montreal, Quebec H2X 4A5, Canada

The structure of human BCL-w, an anti-apoptotic member of the BCL-2 family, was determined by triple-resonance NMR spectroscopy and molecular modeling. Introduction of a single amino acid substitution (P117V) significantly improved the quality of the NMR spectra obtained. The cytosolic domain of BCL-w consists of 8 -helices, which adopt a fold similar to that of BCL-x_L, BCL-2, and BAX proteins. Pairwise root meant square deviation values were less than 3 Å for backbone atoms of structurally equivalent regions. Interestingly, the C-terminal helix 8 of BCL-w folds into the BH3-binding hydrophobic cleft of the protein, in a fashion similar to the C-terminal transmembrane helix of BAX. A peptide corresponding to the BH3 region of the pro-apoptotic protein, BID, could displace helix 8 from the BCL-w cleft, resulting in helix unfolding. Deletion of helix 8 increased binding affinities of BCL-w for BAK and BID BH3-peptides, indicating that this helix competes for peptide binding to the hydrophobic cleft. These results suggest that although the cytosolic domain of BCL-w exhibits an overall structure similar to that of BCL-x_L and BCL-2, the unique organization of its C-terminal helix may modulate BCL-w interactions with pro-apoptotic binding partners.

Received for publication, February 19, 2003 , and in revised form, March 21, 2003.

The atomic coordinates and structure factors (code 1MK3) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by a Natural Science and Engineering Research Council of Canada partnership grant (to K. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada. Tel.: 514-398-7287; Fax: 514-398-7384; E-mail: kalle.gehring{at}mcgill.ca.

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