The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4

Open Access
Publisher Website
Google Scholar
Abstract
Bcl‐2 and close homologues such as Bcl‐xL promote cell survival, while other relatives such as Bax antagonize this function. Since only the pro‐survival family members possess a conserved N‐terminal region denoted BH4, we have explored the role of this amphipathic helix for their survival function and for interactions with several agonists of apoptosis, including Bax and CED‐4, an essential regulator in the nematode Caenorhabditis elegans . BH4 of Bcl‐2 could be replaced by that of Bcl‐x without perturbing function but not by a somewhat similar region near the N‐terminus of Bax. Bcl‐2 cell survival activity was reduced by substitutions in two of ten conserved BH4 residues. Deletion of BH4 rendered Bcl‐2 (and Bcl‐xL) inactive but did not impair either Bcl‐2 homodimerization or ability to bind to Bax or five other pro‐apoptotic relatives (Bak, Bad, Bik, Bid or Bim). Hence, association with these death agonists is not sufficient to promote cell survival. Significantly, however, Bcl‐xL lacking BH4 lost the ability both to bind CED‐4 and antagonize its pro‐apoptotic activity. These results favour the hypothesis that the BH4 domain of pro‐survival Bcl‐2 family members allows them to sequester CED‐4 relatives and thereby prevent apoptosis.