MAP-1 Is a Putative Ligand for the Multidomain Proapoptotic Protein Bax

Abstract

Recent data on gene deletion analyses revealed that cells derived from animals that are deficient in both Bax and Bak (two key members of the "multidomain" proapoptotic Bcl-2 subfamily), but not cells lacking one of the two genes, are completely resistant to apoptotic death triggered by diverse stimuli. These data suggest that engagement of a "multidomain" proapoptotic member, BAX or BAK, is essential for apoptotic signaling. To gain further understanding of the molecular functions of the "multidomain" proapoptotic molecules, we used yeast two hybrid screen to identify protein partners of BAX. A proapoptotic protein, termed MAP-1 (Modulator of Apoptosis), was identified as a BAX-interacting protein from a human brain cDNA library. MAP-1 is a member of a growing family of proteins that were initially identified as onconeural antigens. MAP-1 contains a BH3-like motif and mediates caspase-dependent death in mammalian cells when overexpressed. Mutagenesis analyses revealed that the BH3-like domain of MAP-1 is required for association with BAX and for mediating apoptosis. Interestingly, in contrast to all other previously identified BAX-associating proteins that require only one of the three BH domains of BAX for binding, all the three BH (BH1, BH2 and BH3) domains of BAX are necessary for binding to MAP-1. Taken together, these data suggest that MAP-1 may mediate its proapoptotic function by engaging its BH3-like domain in binding the BCI-X-L-like hydrophobic pocket of BAX.