Solution structure of human BCL-w: modulation of ligand binding by the C-terminal helix

J Biol Chem. 2003 Jun 6;278(23):21124-8. doi: 10.1074/jbc.M301798200. Epub 2003 Mar 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apoptosis Regulatory Proteins
  • Cytosol
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Molecular Sequence Data
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Proteins / chemistry*
  • Proteins / genetics*
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / chemistry
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • bcl-X Protein


  • Apoptosis Regulatory Proteins
  • BCL2L1 protein, human
  • BCL2L2 protein, human
  • Ligands
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein

Associated data

  • PDB/1MK3