School of Medicine, Sun Yat-Sen University, Guangzhou 510275, China.
Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China.
J Mol Biol. 2021 Jun 25;433(13):166989. doi: 10.1016/j.jmb.2021.166989. Epub 2021 Apr 16.
DEP domain containing mTOR-interacting protein (DEPTOR) plays pivotal roles in regulating metabolism, growth, autophagy and apoptosis by functions as an endogenous inhibitor of mTOR signaling pathway. Activated by phosphatidic acid, a second messenger in mTOR signaling, DEPTOR dissociates from mTORC1 complex with unknown mechanism. Here, we present a 1.5 Å resolution crystal structure, which shows that the N-terminal two tandem DEP domains of hDEPTOR fold into a dumbbell-shaped structure, protruding the characteristic β-hairpin arms of DEP domains on each side. An 18 amino acids DDEX motif at the end of DEP2 interacts with DEP1 and stabilizes the structure. Biochemical studies showed that the tandem DEP domains directly interact with phosphatidic acid using two distinct positively charged patches. These results provide insights into mTOR activation upon phosphatidic acid stimulation.
DEP 结构域包含的 mTOR 相互作用蛋白（DEPTOR）通过作为 mTOR 信号通路的内源性抑制剂，在调节代谢、生长、自噬和凋亡方面发挥关键作用。DEP 受 mTOR 信号的第二信使磷脂酸激活，通过未知的机制与 mTORC1 复合物解离。在这里，我们呈现了一个分辨率为 1.5Å 的晶体结构，该结构显示 hDEPTOR 的 N 端两个串联 DEP 结构域折叠成哑铃状结构，在每一侧突出 DEP 结构域的特征 β-发夹臂。DEP2 末端的 18 个氨基酸 DDEX 基序与 DEP1 相互作用并稳定结构。生化研究表明，串联 DEP 结构域使用两个独特的正电荷斑直接与磷脂酸相互作用。这些结果为磷脂酸刺激后 mTOR 的激活提供了见解。
