Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlateswith their ability to bind pro-apoptotic family members

Certain Bcl-2 family members promote cell survival, whereas others promote apoptosis, To explore further how heterodimerization of opposing members af fects survival activity, we have compared the abilities of the anti-apoptot ic Bcl-w and Al to bind to the pro-apoptotic Bax, Bak, Bad and Bik and to p rotect cells from their cytotoxic action. Bcl-w co-immunoprecipitated from cell lysates with Bax, Bak, Bad and Bik, but Al bound only Bak and Bik, Mut ation of Al at a highly conserved glycine within the BH1 domain prevented b inding, but the comparable Bcl-w mutant still bound Bak, Bad and Bik, indic ating that the glycine is not essential for all heterodimerization, Bcl-w a nd Al protected against apoptosis induced by over-expression of Bax or Bad but not that induced by Bak or Bik, With several gene pairs, binding and pr otection were discordant. The results may reflect critical threshold affini ties but also suggest that certain pro-apoptotic proteins may also contribu te to apoptosis by a mechanism independent of binding pro-survival proteins .