BID - A NOVEL BH3 DOMAIN-ONLY DEATH AGONIST

The BCL-2 family of proteins consists of both antagonists (e.g., BCL-2 ) and agonists (e.g., BAX) that regulate apoptosis and compete through dimerization. The BH1 and BH2 domains of BCL-2 are required to hetero dimerize with BAX and to repress cell death; conversely, the BH3 domai n of BAX is required to heterodimerize with BCL-2 and to promote cell death. To extend this pathway, we used interactive cloning to identify Bid, which encodes a novel death agonist that heterodimerizes with ei ther agonists (BAX) or antagonists (BCL-2). BID possesses only the BH3 domain, lacks a carboxy-terminal signal-anchor segment, and is found in both cytosolic and membrane locations. BID counters the protective effect of BCL-2. Moreover, expression of BID, without another death st imulus, induces ICE-like proteases and apoptosis. Mutagenesis revealed that an intact BH3 domain of BID was required to bind the BH1 domain of either BCL-2 or BAX. A BH3 mutant of BID that still heterodimerized with BCL-2 failed to promote apoptosis, dissociating these activities . In contrast, the only BID BH3 mutant that retained death promoting a ctivity interacted with BAX, but not BCL-2. This BH3-only molecule sup ports BH3 as a death domain and favors a model in which BID represents a death ligand for the membrane-bound receptor BAX.