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

      The EMBO Journal
      Amino Acid Sequence, Apoptosis, drug effects, genetics, Apoptosis Regulatory Proteins, BH3 Interacting Domain Death Agonist Protein, Caenorhabditis elegans Proteins, Calcium-Binding Proteins, antagonists & inhibitors, metabolism, Carrier Proteins, Cell Line, Conserved Sequence, Dimerization, Helminth Proteins, Humans, Membrane Proteins, Molecular Sequence Data, Protein Binding, Protein Structure, Tertiary, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, chemistry, 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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          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.

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