title: Solution structure of human BCL-w: modulation of ligand binding by the C-terminal helix.
abstract: 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 alpha-helices, which adopt a fold similar to that of BCL-xL, BCL-2, and BAX proteins. Pairwise root meant square deviation values were less than 3 A for backbone atoms of structurally equivalent regions. Interestingly, the C-terminal helix alpha8 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 alpha8 from the BCL-w cleft, resulting in helix unfolding. Deletion of helix alpha8 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-xL and BCL-2, the unique organization of its C-terminal helix may modulate BCL-w interactions with pro-apoptotic binding partners.
authors.affiliation: Department of Biochemistry and Montreal Joint Center for Structural Biology, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Alexei Yu
authors.initials: AY
authors.lastname: Denisov
authors.forename: Murthy S R
authors.initials: MS
authors.lastname: Madiraju
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Abdelkrim
authors.initials: A
authors.lastname: Khadir
authors.forename: Pierre
authors.initials: P
authors.lastname: Beauparlant
authors.forename: Giorgio
authors.initials: G
authors.lastname: Attardo
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Shore
authors.forename: Kalle
authors.initials: K
authors.lastname: Gehring
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D003600:Cytosol; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C491073:BCL2L2 protein, human; D008024:Ligands; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein