BID: A novel BH3 domain-only death agonist
BID: A novel BH3 domain-only death agonist
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DOI：
10.1101/gad.10.22.2859
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发表时间：
1996-11-15
影响因子：
10.5
通讯作者：
Korsmeyer, SJ
中科院分区：
文献类型：
--
作者：
Wang, K;Yin, XM;Korsmeyer, SJ
蛋白质的Bcl-2家族由拮抗剂（例如Bcl-2）和激动剂（例如Bax）组成，这些拮抗剂（例如Bax）通过二聚化来调节凋亡并竞争。需要Bcl-2的BH1和BH2结构域与Bax异二聚并抑制细胞死亡。相反，需要BAX的BH3结构域与Bcl-2异构二聚体并促进细胞死亡。为了扩展这一途径，我们使用交互式克隆来识别出价，该竞标编码了一种新型的死亡激动剂，该死亡激动剂与激动剂（Bax）或拮抗剂（BCL-2）异二聚体。投标只有BH3结构域，缺少羧基末端信号锚节段，并且在胞质和膜位置都可以找到。出价反驳了Bcl-2的保护作用。此外，出价的表达，没有其他死亡刺激，会诱导冰状蛋白酶和凋亡。诱变表明，需要出价的完整BH3结构域来结合Bcl-2或Bax的BH1结构域。仍然被BCL-2异二聚体的BH3突变体未能促进凋亡，从而解散了这些活性。相比之下，保留死亡活性的唯一出价BH3突变体与BAX相互作用，但与Bcl-2相互作用。这种仅BH3的分子支持BH3作为死亡结构域，并有利于竞标代表膜结合受体Bax的死亡配体的模型。
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.