对人类系统yL氨基酸转运体复合物的结构见解。

Structural insights into the human system yL amino acid transporter complex.

作者信息

Dai Lu, Xu Kangtai, Zhang Ting, Wang Xiaoting, Zeng Qian, Liang Hao, Xu Chenye, Yang Liuqing, Wang Zilong, Yan Renhong

机构信息

SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong Province, China; Key University Laboratory of Metabolism and Health of Guangdong, Institute for Biological Electron Microscopy, Southern University of Science and Technology, Shenzhen, Guangdong Province, China.

出版信息

Structure. 2025 Apr 27. doi: 10.1016/j.str.2025.04.012.

DOI:10.1016/j.str.2025.04.012

PMID:40347950

Abstract

System yL facilitates the sodium-independent transport of cationic and sodium-dependent transport of neutral amino acids via heteromeric amino acid transporters. System yL consists of either SLC7A6 (yLAT2) or SLC7A7 (yLAT1) and 4F2hc (SLC3A2). The yLAT2-4F2hc complex mediates the exchange of -lysine (Lys), -arginine (Arg), -leucine (Leu), and -glutamine (Gln) and is important for the glutamate-glutamine cycle and ammonia clearance. c-Myc-driven upregulation of yLAT2 in cancer enhances amino acid uptake and mTORC1 activation, promoting tumor growth. Its transport mechanism has remained unclear. Here, we determined the cryoelectron microscopic (cryo-EM) structures of the yLAT2-4F2hc complex bound to either Arg or Leu at 3.60 Å and 3.58 Å resolution, respectively, revealing an outward-open conformation. Our structural analysis highlights conformational changes during transport, and functional assays validate critical residues involved in substrate binding and transport. These findings elucidate the molecular mechanism of the system yL and provide a foundation for developing targeted therapies against yLAT2.

摘要

yL 系统通过异源氨基酸转运体促进阳离子的非钠依赖性转运和中性氨基酸的钠依赖性转运。yL 系统由 SLC7A6（yLAT2）或 SLC7A7（yLAT1）以及 4F2hc（SLC3A2）组成。yLAT2 - 4F2hc 复合物介导赖氨酸（Lys）、精氨酸（Arg）、亮氨酸（Leu）和谷氨酰胺（Gln）的交换，对谷氨酸 - 谷氨酰胺循环和氨清除至关重要。c - Myc 驱动的癌症中 yLAT2 的上调增强了氨基酸摄取和 mTORC1 激活，促进肿瘤生长。其转运机制尚不清楚。在这里，我们分别以 3.60 Å 和 3.58 Å 的分辨率确定了与 Arg 或 Leu 结合的 yLAT2 - 4F2hc 复合物的冷冻电子显微镜（cryo - EM）结构，揭示了向外开放的构象。我们的结构分析突出了转运过程中的构象变化，功能测定验证了参与底物结合和转运的关键残基。这些发现阐明了 yL 系统的分子机制，并为开发针对 yLAT2 的靶向疗法提供了基础。