PMID:9463381

Citation	Huang, DC, Adams, JM and Cory, S (1998) The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4. EMBO J. 17:1029-39
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.
Links	PubMed PMC1170452 Online version:10.1093/emboj/17.4.1029
Keywords	Amino Acid Sequence; Apoptosis/drug effects; Apoptosis/genetics; Apoptosis Regulatory Proteins; BH3 Interacting Domain Death Agonist Protein; Caenorhabditis elegans Proteins; Calcium-Binding Proteins/antagonists & inhibitors; Calcium-Binding Proteins/metabolism; Carrier Proteins/metabolism; Cell Line; Conserved Sequence; Dimerization; Helminth Proteins/antagonists & inhibitors; Helminth Proteins/metabolism; Humans; Membrane Proteins/metabolism; Molecular Sequence Data; Protein Binding; Protein Structure, Tertiary; Proteins/metabolism; Proto-Oncogene Proteins/metabolism; Proto-Oncogene Proteins c-bcl-2/chemistry; Proto-Oncogene Proteins c-bcl-2/genetics; Proto-Oncogene Proteins c-bcl-2/metabolism; Proto-Oncogene Proteins c-bcl-2/physiology; Sequence Deletion; Sequence Homology, Amino Acid; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; bcl-Associated Death Protein; bcl-X Protein
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