Bcl-XL Mutations Suppress Cellular Sensitivity to Antimycin A

Cells expressing high levels of the BCL-XL 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-XL, previously identified as an interface for dimerization to BAX and related proapoptotic proteins. Here, we identify BCL-XL hydrophobic groove mutants with normal cellular anti-apoptotic function but suppressed sensitivity to AA. The LD50 of AA for cells expressing BCL-XL mutants directly correlates with the measured in vitro dissociation constants for AA binding. These results indicate that BCL-XL is a principal target mediating AA cytotoxicity.