Bim蛋白促凋亡活性必需核心元件的识别与研究(英文)

Identification of the Bim Core Unit for Pro-apoptotic Activity

在之前的研究中,我们寻找并克隆到了一个新的Bim异构体Bimβ5,其转录从开放阅读框的第2个ATG起始,并编码一个包含BH3结构域的36个氨基酸的蛋白质.BH3结构域被认为是Bim蛋白及其他Bcl-2家族蛋白发挥作用的充分必要条件,因此有必要探寻其序列中对Bim蛋白功能起决定作用的核心区域.通过设计并构建基于Bimβ5的开放阅读框的一系列截断体,检测不同截断体的促凋亡能力,最终得到了Bim蛋白发挥功能所需的最短保守序列,即包含17个氨基酸的序列QELRRIGDEFNAYYARR,并将其命名为Bim核心元件.此外,通过对只包含Bim核心元件的截断体Bimβ5A3进行计算机分子建模,进一步揭示了Bim核心元件促凋亡的作用机理.Bim核心元件在介导Bak/Bax形成同源或异源二聚体时发挥着重要作用.

In previous study, we have cloned a novel transcript of Bim, Bim135, of which the open reading frame may initiate at the second ATG and encodes a 36 amino-acid peptide with BH3 domain. As BH3 domain is essential for the functions of Bim and other Bcl-2 family proteins, it is necessary to determine its minimal functional sequence. A series of truncated versions of Bim[35 were constructed and a 17-residue fragment （QELRRIGDEFNAYYARR, denoted as the Bim core unit or BCU） was identified as the minimal consensus sequence for Bim＇s pro-apoptotic activity. Computational molecular modeling was used to understand the mechanism by which apoptosis is induced by Bimβ5A3, a pro-apoptotic construct of Bimβ5 consisting mainly of the BCU. The modeling suggests that the BCU may play a role in the homo-or hetero-dimerization of Bak/Bax.