title: BID: a novel BH3 domain-only death agonist.
abstract: 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 heterodimerize with BAX and to repress cell death; conversely, the BH3 domain 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 either 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 stimulus, 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 activity interacted with BAX, but not BCL-2. This BH3-only molecule supports BH3 as a death domain and favors a model in which BID represents a death ligand for the membrane-bound receptor BAX.
authors.affiliation: Department of Medicine and Pathology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: K
authors.initials: K
authors.lastname: Wang
authors.forename: X M
authors.initials: XM
authors.lastname: Yin
authors.forename: D T
authors.initials: DT
authors.lastname: Chao
authors.forename: C L
authors.initials: CL
authors.lastname: Milliman
authors.forename: S J
authors.initials: SJ
authors.lastname: Korsmeyer
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D020170:Caspase 1; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000096:biosynthesis; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004790:Enzyme Induction; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013045:Species Specificity; D051028:bcl-2-Associated X Protein
chemical_list: D000590:Amino Acid Chloromethyl Ketones; C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C494827:Bax protein, mouse; C494815:Bid protein, mouse; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D003546:Cysteine Endopeptidases; D020170:Caspase 1