Department of Chemistry, University of Umeå, Umeå, Sweden.
ISIS Pulsed Neutron and Muon Source, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Science&Innovation Campus, Didcot, Oxfordshire, UK.
Commun Biol. 2021 Apr 27;4(1):507. doi: 10.1038/s42003-021-02032-1.
B-cell lymphoma 2 (Bcl-2) proteins are the main regulators of mitochondrial apoptosis. Anti-apoptotic Bcl-2 proteins possess a hydrophobic tail-anchor enabling them to translocate to their target membrane and to shift into an active conformation where they inhibit pro-apoptotic Bcl-2 proteins to ensure cell survival. To address the unknown molecular basis of their cell-protecting functionality, we used intact human Bcl-2 protein natively residing at the mitochondrial outer membrane and applied neutron reflectometry and NMR spectroscopy. Here we show that the active full-length protein is entirely buried into its target membrane except for the regulatory flexible loop domain (FLD), which stretches into the aqueous exterior. The membrane location of Bcl-2 and its conformational state seems to be important for its cell-protecting activity, often infamously upregulated in cancers. Most likely, this situation enables the Bcl-2 protein to sequester pro-apoptotic Bcl-2 proteins at the membrane level while sensing cytosolic regulative signals via its FLD region.
B 细胞淋巴瘤 2（Bcl-2）蛋白是线粒体凋亡的主要调节因子。抗凋亡 Bcl-2 蛋白具有疏水性尾部锚定，使它们能够转移到靶膜，并转变为活性构象，在该构象中，它们抑制促凋亡 Bcl-2 蛋白，以确保细胞存活。为了解决其细胞保护功能的未知分子基础，我们使用天然存在于线粒体外膜的完整人 Bcl-2 蛋白，并应用中子反射和 NMR 光谱。在这里，我们表明活性全长蛋白完全埋入其靶膜中，除了调节灵活环结构域（FLD）外，该结构域延伸到水相外部。Bcl-2 的膜定位及其构象状态似乎对其细胞保护活性很重要，这种活性在癌症中经常被上调。很可能，这种情况使 Bcl-2 蛋白能够在膜水平上隔离促凋亡 Bcl-2 蛋白，同时通过其 FLD 区域感知细胞质调节信号。
