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首页> 外文期刊>Molecular and Cellular Biology >Identification of Novel Isoforms of the BH3 Domain Protein Bim Which Directly Activate Bax To Trigger Apoptosis
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Identification of Novel Isoforms of the BH3 Domain Protein Bim Which Directly Activate Bax To Trigger Apoptosis

机译：直接激活Bax触发凋亡的BH3域蛋白Bim的新型同工型的鉴定。

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摘要

Bim (Bcl-2-interacting mediator of cell death) is a member of the BH3 domain-only subgroup of Bcl-2 family members, for which three splice variants have been described. Bim is expressed in many healthy cell types, where it is maintained in an inactive conformation through binding to the microtubule-associated dynein motor complex. Upon certain apoptotic stimuli, Bim is released from microtubules and mediates caspase-dependent apoptosis through a mechanism that is still unclear. Here, we have identified and characterized novel splice variants of human Bim mRNA. In particular, we show that a newly discovered, small protein isoform, BimAD, is also able to induce apoptosis strongly in several human cell lines. BimAD and the previously characterized isoform BimS are shown to be capable of heterodimerizing in vivo with both death antagonists (Bcl-2 and Bcl-XL) and death agonists (Bax). Mutants of BimAD that bind to Bax but not to Bcl-2 still promote apoptosis, indicating that Bim can regulate apoptosis through direct activation of the Bax-mediated cell death pathway without interaction with antiapoptotic Bcl-2 family members. Furthermore, we have shown that the interaction of the BimS and BimAD isoforms with Bax leads to a conformational change in this protein analogous to that triggered by the BH3-only protein Bid.
机译：Bim（细胞死亡的Bcl-2相互作用介质）是Bcl-2家族成员的仅BH3结构域亚组的成员，已针对其描述了三个剪接变体。 Bim在许多健康的细胞类型中表达，通过与微管相关的动力蛋白运动复合物结合，使其维持在非活性状态。在某些凋亡刺激下，Bim从微管释放，并通过尚不清楚的机制介导caspase依赖性凋亡。在这里，我们已经鉴定并鉴定了人类Bim mRNA的新型剪接变体。特别是，我们显示了新发现的小蛋白同种型BimAD，也能够在几种人类细胞系中强烈诱导凋亡。 BimAD和先前表征的同工型BimS被证明能够与死亡拮抗剂（Bcl-2和Bcl-X L ）和死亡激动剂（Bax）在体内异二聚化。与Bax结合但不与Bcl-2结合的BimAD突变体仍然促进细胞凋亡，表明Bim可以通过直接激活Bax介导的细胞死亡途径而不与抗凋亡Bcl-2家族成员相互作用来调节细胞凋亡。此外，我们已经表明，BimS和BimAD同工型与Bax的相互作用导致该蛋白质的构象变化，类似于仅由BH3蛋白质Bid触发的构象变化。

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