State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 132 Lanhei Road, Heilongtan, Kunming, 650201, Yunnan, China; Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
Biochem Biophys Res Commun. 2022 Aug 30;617(Pt 2):1-6. doi: 10.1016/j.bbrc.2022.05.086. Epub 2022 May 29.
The formation of death-inducing signaling complex (DISC) and death effector domain (DED) filament initiates extrinsic apoptosis. Recruitment and activation of procaspase-8 at the DISC are regulated by c-FLIP. The interaction between c-FLIP and procaspase-8 is mediated by their tandem DEDs (tDED). However, the structure of c-FLIP and how c-FLIP interferes with procaspase-8 activation at the DISC remain elusive. Here, we solved the monomeric structure of c-FLIP (F114G) at near physiological pH by solution nuclear magnetic resonance (NMR). Structural superimposition reveals c-FLIP (F114G) adopts a structural topology similar to that of procaspase-8. Our results provide a structural basis for understanding how c-FLIP interacts with procaspase-8 and the molecular mechanisms of c-FLIP in regulating cell death.
死亡诱导信号复合物（DISC）和死亡效应结构域（DED）纤维的形成引发外在细胞凋亡。DISC 处的前胱天蛋白酶-8 的募集和激活受 c-FLIP 调节。c-FLIP 和前胱天蛋白酶-8 之间的相互作用由它们的串联 DED（tDED）介导。然而，c-FLIP 的结构以及 c-FLIP 如何在 DISC 处干扰前胱天蛋白酶-8 的激活仍然难以捉摸。在这里，我们通过溶液核磁共振（NMR）在接近生理 pH 的条件下解决了 c-FLIP（F114G）的单体结构。结构叠加显示 c-FLIP（F114G）采用与前胱天蛋白酶-8 相似的结构拓扑。我们的结果为理解 c-FLIP 如何与前胱天蛋白酶-8 相互作用以及 c-FLIP 在调节细胞死亡中的分子机制提供了结构基础。
