title: Bcl-XL mutations suppress cellular sensitivity to antimycin A.
abstract: Cells expressing high levels of the BCL-X(L) anti-apoptotic protein are preferentially killed by the mitochondrial inhibitor antimycin A (AA). Computational modeling predicts a binding site for AA in the extended hydrophobic groove on BCL-X(L), previously identified as an interface for dimerization to BAX and related proapoptotic proteins. Here, we identify BCL-X(L) hydrophobic groove mutants with normal cellular anti-apoptotic function but suppressed sensitivity to AA. The LD(50) of AA for cells expressing BCL-X(L) mutants directly correlates with the measured in vitro dissociation constants for AA binding. These results indicate that BCL-X(L) is a principal target mediating AA cytotoxicity.
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Manion
authors.forename: Jason W
authors.initials: JW
authors.lastname: O'Neill
authors.forename: Chris D
authors.initials: CD
authors.lastname: Giedt
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Kim
authors.forename: Kam Y Z
authors.initials: KY
authors.lastname: Zhang
authors.forename: David M
authors.initials: DM
authors.lastname: Hockenbery
mesh_terms: D000595:Amino Acid Sequence; D000968:Antimycin A / Q000494:pharmacology*; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions; D008969:Molecular Sequence Data; D017354:Point Mutation; D017510:Protein Folding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000502:physiology; D051020:bcl-X Protein
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D000968:Antimycin A