Apoptosis is a naturally occurring process during the growth and development of multicellular organisms and is increasingly active during times of cellular stress such as in response to intracellular DNA damage when removal of the host cell is paramount to prevent cancer. Unfortunately, once formed, cancer cells become impervious to apoptosis, creating a desperate need to identify an approach to induce apoptosis in these cells. An attractive option is to focus efforts on developing and locating compounds which activate apoptosis using natural compounds. Curcumin is a natural component in turmeric and is well-known for its pharmacological effects in preventing and combating many ailments and has been shown to decrease the rapid proliferation of a wide variety of tumor cells. However, to date, the apoptotic intermediates and interactions through which curcumin exerts its cytotoxic effects are unknown. Motivated by reports linking the intracellular modulation of the concentrations of Bid and Bcl-xL, following curcumin administration to cancer cells, we set out to probe for potential intermolecular interactions of these proteins with curcumin. Using several biophysical techniques, most notably, fluorescence, circular dichroism and nuclear magnetic resonance spectroscopy, we reveal binding interactions of curcumin with both Bcl-xLΔC and full-length Bid (Bid-FL) and prove that this binding is hydrophobically driven and localized to well-known functional regions of each protein. Specifically, our NMR studies show that while Bid-FL interacts with curcumin through its hydrophobic and pore forming helices (α6-α7), Bcl-xLΔC interacts with curcumin via its BH3 binding pocket (α2-α3-α4-α5), a critical region for mediating apoptosis.

中文翻译：

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姜黄素，一种通过与 Bcl-xL 和 Bid 直接相互作用而引起细胞凋亡的潜在引发剂

细胞凋亡是多细胞生物生长和发育过程中自然发生的过程，并且在细胞应激期间变得越来越活跃，例如在去除宿主细胞对于预防癌症至关重要时响应细胞内 DNA 损伤。不幸的是，一旦形成，癌细胞就不会受到细胞凋亡的影响，因此迫切需要确定一种方法来诱导这些细胞发生细胞凋亡。一个有吸引力的选择是集中精力开发和定位使用天然化合物激活细胞凋亡的化合物。姜黄素是姜黄中的一种天然成分，以其在预防和对抗许多疾病方面的药理作用而闻名，并已被证明可以减少多种肿瘤细胞的快速增殖。然而，迄今为止，姜黄素发挥其细胞毒性作用的凋亡中间体和相互作用尚不清楚。受报告将Bid和Bcl-xL浓度的细胞内调节联系起来，在姜黄素对癌细胞给药后，我们着手探索这些蛋白质与姜黄素的潜在分子间相互作用。使用几种生物物理技术，最值得注意的是荧光、圆二色性和核磁共振光谱，我们揭示了姜黄素与 Bcl-xLΔC 和全长 Bid (Bid-FL) 的结合相互作用，并证明这种结合是疏水驱动的并定位于每个蛋白质的众所周知的功能区域。具体来说，我们的 NMR 研究表明，虽然 Bid-FL 通过其疏水和成孔螺旋 (α6-α7) 与姜黄素相互作用，