Bad is a BH3 domain-containing protein that forms an inactivating dimer with Bcl-x(L)
Bad is a BH3 domain-containing protein that forms an inactivating dimer with Bcl-x(L)
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DOI：
10.1128/mcb.17.12.7040
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发表时间：
1997-12-01
影响因子：
5.3
通讯作者：
Thompson, CB
中科院分区：
文献类型：
--
作者：
Kelekar, A;Chang, BS;Thompson, CB
Bcl-2相关蛋白Bad是凋亡的启动子，并且已经显示与抗凋亡蛋白Bcl-2和Bcl-x（L）二聚化。Bad在小鼠FL5.12细胞中的过表达表明，该蛋白不仅可以消除共表达的Bcl-x（L）的保护能力，而且当其在缺乏外源性Bcl-x（L）的情况下表达时，可以加速对死亡信号的凋亡反应。使用缺失分析，我们已经鉴定了鼠Bad蛋白中可以与Bcl-x（L）二聚化的最小结构域。发现该结构域内的26个氨基酸的肽是结合Bcl-x（L）所必需的，并且足以结合Bcl-x（L），所述肽显示出与相关凋亡蛋白如巴克和Bax的α-螺旋BH 3结构域的显著同源性。为了确定二聚化在调节Bad的死亡促进活性和Bcl-x（L）的死亡抑制活性中的作用，测试Bcl-x（L）中的疏水BH 3结合口袋内的突变在Bad存在下促进细胞存活的能力，所述突变消除了Bcl-x（L）与Bad形成异源二聚体的能力。这些突变体中的几个保留了赋予针对细胞死亡的保护的能力，而不管共表达的Bad蛋白的水平如何。这些结果表明，Bad等含BH 3的蛋白质通过与Bcl-2家族的抗凋亡成员结合，从而抑制其生存促进功能，从而促进细胞死亡。
The Bcl-2 related protein Bad is a promoter of apoptosis and has been shown to dimerize with the anti-apoptotic proteins Bcl-2 and Bcl-x(L). Overexpression of Bad in murine FL5.12 cells demonstrated that the protein not only could abrogate the protective capacity of coexpressed Bcl-x(L) but could accelerate the apoptotic response to a death signal when it was expressed in the absence of exogenous Bcl-x(L). Using deletion analysis, we have identified the minimal domain in the murine Bad protein that can dimerize with Bcl-x(L). A 26-amino-acid peptide within this domain, which showed significant homology to the alpha-helical BH3 domains of related apoptotic proteins like Bak and Bax, was found to be necessary and sufficient to bind Bcl-x(L). To determine the role of dimerization in regulating the death-promoting activity of Bad and the death-inhibiting activity of Bcl-x(L), mutations within the hydrophobic BH3-binding pocket in Bcl-x(L) that eliminated the ability of Bcl-x(L) to form a heterodimer with Bad were tested for the ability to promote cell survival in the presence of Bad. Several of these mutants retained the ability to impart protection against cell death regardless of the level of coexpressed Bad protein. These results suggest that BH3-containing proteins like Bad promote cell death by binding to antiapoptotic members of the Bcl-2 family and thus inhibiting their survival promoting functions.