Rajan Sreekanth, Choi Minjoo, Baek Kwanghee, Yoon Ho Sup
School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore.
Department of Genetic Engineering, College of Life Sciences, Kyung Hee University, Yongin-Si, Gyeonggi-Do, 446-701, Republic of Korea.
Proteins. 2015 Jul;83(7):1262-72. doi: 10.1002/prot.24816. Epub 2015 May 23.
Apoptosis or programmed cell death is a regulatory process in cells in response to stimuli perturbing physiological conditions. The Bcl-2 family of proteins plays an important role in regulating homeostasis during apoptosis. In the process, the molecular interactions among the three members of this family, the pro-apoptotic, anti-apoptotic and BH3-only proteins at the mitochondrial outer membrane define the fate of a cell. Here, we report the crystal structures of the human anti-apoptotic protein Bcl-XL in complex with BH3-only BID(BH3) and BIM(BH3) peptides determined at 2.0 Å and 1.5 Å resolution, respectively. The BH3 peptides bind to the canonical hydrophobic pocket in Bcl-XL and adopt an alpha helical conformation in the bound form. Despite a similar structural fold, a comparison with other BH3 complexes revealed structural differences due to their sequence variations. In the Bcl-XL-BID(BH3) complex we observed a large pocket, in comparison with other BH3 complexes, lined by residues from helices α1, α2, α3, and α5 located adjacent to the canonical hydrophobic pocket. These results suggest that there are differences in the mode of interactions by the BH3 peptides that may translate into functional differences in apoptotic regulation.
细胞凋亡或程序性细胞死亡是细胞针对扰乱生理条件的刺激所做出的一种调节过程。Bcl-2蛋白家族在细胞凋亡过程中调节体内平衡方面发挥着重要作用。在此过程中，该家族三个成员（促凋亡蛋白、抗凋亡蛋白和仅含BH3结构域的蛋白）在线粒体外膜的分子相互作用决定了细胞的命运。在此，我们报告了人抗凋亡蛋白Bcl-XL分别与仅含BH3结构域的BID（BH3）和BIM（BH3）肽形成的复合物的晶体结构，分辨率分别为2.0 Å和1.5 Å。BH3肽与Bcl-XL中的典型疏水口袋结合，并以结合形式呈现α螺旋构象。尽管结构折叠相似，但与其他BH3复合物相比，由于序列差异，它们在结构上存在不同。在Bcl-XL-BID（BH3）复合物中，与其他BH3复合物相比，我们观察到一个大口袋，由位于典型疏水口袋附近的α1、α2、α3和α5螺旋的残基构成。这些结果表明，BH3肽的相互作用模式存在差异，这可能转化为凋亡调节中的功能差异。
