title: The structure of Bcl-w reveals a role for the C-terminal residues in modulating biological activity.
abstract: 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-x(L) 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-x(L). 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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Hinds
authors.forename: Martin
authors.initials: M
authors.lastname: Lackmann
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Skea
authors.forename: Penny J
authors.initials: PJ
authors.lastname: Harrison
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Day
mesh_terms: D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D051020:bcl-X Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C491073:BCL2L2 protein, human; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein