Bcl-XL mutations suppress cellular sensitivity to antimycin A.
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.
Manion
Michael K
MK
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
O'Neill
Jason W
JW
Giedt
Chris D
CD
Kim
Kristine M
KM
Zhang
Kam Y Z
KY
Hockenbery
David M
DM
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
D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D000968:Antimycin A