Apoptosis is regulated by evolutionarily conserved signaling pathways to remove damaged, diseased or unwanted cells. Proteins homologous to the B-cell lymphoma 2 (Bcl-2) family of proteins, the primary arbiters of mitochondrially mediated apoptosis, are encoded by the cnidarian Hydra vulgaris. We mapped interactions between pro-survival and pro-apoptotic Bcl-2 proteins of H. vulgaris by affinity measurements between Hy-Bcl-2-4, the sole confirmed pro-survival Bcl-2 protein, with BH3 motif peptides of two Bcl-2 proteins from hydra that displayed pro-apoptotic activity, Hy-Bak1 and Hy-BH3-only-2, and the BH3 motif peptide of the predicted pro-apoptotic protein Hy-Bax. In addition to peptides from hydra encoded pro-apoptotic proteins, Hy-Bcl-2-4 also engaged BH3 motif peptides from multiple human pro-apoptotic Bcl-2 proteins. Reciprocally, human pro-survival Bcl-2 proteins Bcl-2, Bcl-xL, Bcl-w, Mcl-1 and A1/Bfl-1 bound to BH3 spanning peptides from hydra encoded pro-apoptotic Hy-Bak1, Hy-BH3-only and Hy-Bax. The molecular details of the interactions were determined from crystal structures of Hy-Bcl-2-4 complexes with BH3 motif peptides of Hy-Bak1 and Hy-Bax. Our findings suggest that the Bcl-2 family in hydra may function in a manner analogous to the Bcl-2 family in humans, and less like the worm Caenorhabditis elegans where evolutionary gene deletion has simplified the apoptotic program. Combined, our results demonstrate the powerful conservation of the interaction pattern between hydra and human Bcl-2 family members. Furthermore, our data reveal mechanistic differences in the mode of binding between hydra and sponges such as Geodia cydonium, with hydra encoded Bcl-2 resembling the more promiscuous pro-apoptotic Bcl-2 members found in mammals compared with its sponge counterpart.

中文翻译：

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Bcl-2介导的水death细胞死亡调控的结构基础。

通过进化上保守的信号通路来调节细胞凋亡，以去除受损，患病或不需要的细胞。与线粒体介导的细胞凋亡的主要仲裁者B细胞淋巴瘤2（Bcl-2）家族蛋白同源的蛋白是由刺藜编码。我们通过Hy-Bcl-2-4（唯一确认的生存前Bcl-2蛋白）与两个Bcl-的BH3基序肽之间的亲和力测量，绘制了嗜血杆菌的生存前和凋亡前Bcl-2蛋白之间的相互作用。来自hydra的2种蛋白具有促凋亡活性，Hy-Bak1和Hy-BH3-only-2，以及预测的促凋亡蛋白Hy-Bax的BH3基序肽。除了来自hydra编码的促凋亡蛋白的肽外，Hy-Bcl-2-4还与多种人类促凋亡Bcl-2蛋白的BH3基序肽结合。相反，人类生存前Bcl-2蛋白Bcl-2，Bcl-xL，Bcl-w，Mcl-1和A1 / Bfl-1与hydra编码的促凋亡Hy-Bak1，仅Hy-BH3的BH3跨越肽结合Hy-Bax。相互作用的分子细节由Hy-Bcl-2-4与Hy-Bak1和Hy-Bax的BH3基序肽的晶体结构确定。我们的发现表明，水中的Bcl-2家族的功能可能类似于人类中的Bcl-2家族，而不像线虫秀丽隐杆线虫那样，其进化基因缺失简化了凋亡程序。结合起来，我们的结果证明了九头蛇和人类Bcl-2家族成员之间相互作用模式的强大保守性。此外，我们的数据揭示了水合物与海绵（如Geodia cydonium）在结合方式上的机理差异，