Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Departments of Biological Chemistry and Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Structure. 2021 May 6;29(5):426-432.e8. doi: 10.1016/j.str.2020.11.014. Epub 2020 Dec 8.
mTORC1 is a central hub that integrates environmental cues, such as cellular stresses and nutrient availability to modulate metabolism and cellular responses. Recently, SLC38A9, a lysosomal amino acid transporter, emerged as a sensor for luminal arginine and as an activator of mTORC1. The amino acid-mediated activation of mTORC1 is regulated by the N-terminal domain of SLC38A9. Here, we determined the crystal structure of zebrafish SLC38A9 (drSLC38A9) and found the N-terminal fragment inserted deep within the transporter, bound in the substrate-binding pocket where normally arginine would bind. This represents a significant conformational change of the N-terminal domain (N-plug) when compared with our recent arginine-bound structure of drSLC38A9. We propose a ball-and-chain model for mTORC1 activation, where N-plug insertion and Rag GTPase binding with SLC38A9 is regulated by luminal arginine levels. This work provides important insights into nutrient sensing by SLC38A9 to activate the mTORC1 pathways in response to dietary amino acids.
mTORC1 是一个中央枢纽，它整合了环境线索，如细胞应激和营养可用性，以调节代谢和细胞反应。最近，溶酶体氨基酸转运蛋白 SLC38A9 作为腔内精氨酸的传感器和 mTORC1 的激活剂而出现。氨基酸介导的 mTORC1 激活受 SLC38A9 的 N 端结构域调节。在这里，我们确定了斑马鱼 SLC38A9（drSLC38A9）的晶体结构，发现 N 端片段插入转运蛋白内部深处，结合在底物结合口袋中，正常情况下精氨酸会结合在该口袋中。与我们最近的 drSLC38A9 结合精氨酸的结构相比，这代表了 N 端结构域（N-塞）的显著构象变化。我们提出了一种 mTORC1 激活的球链模型，其中 N 塞插入和 Rag GTP 酶与 SLC38A9 的结合受腔内精氨酸水平的调节。这项工作为 SLC38A9 对营养物质的感应提供了重要的见解，以响应膳食氨基酸激活 mTORC1 途径。
