LAT1-4F2hc 复合物底物识别与转运机制的研究

氨基酸在维持生命运行中扮演着不可或缺的角色。除了构成蛋白质外，它们还参与了代谢、信号传导以及细胞结构的维持等关键生物功能。氨基酸的代谢紊乱往往会导致多种疾病的发生，包括苯丙酮尿症、帕金森病和癌症等。在氨基酸的运输过程中，转运蛋白 LAT1（ SLC7A5）与其伴侣蛋白 4F2hc（ SLC3A2）形成的异二聚体起着重要作用。 近年来，许多研究表明 LAT1 除了在癌症、肥胖、糖尿病等疾病中的异常表达与疾病的发生和发展密切相关， 其在各种活跃的免疫细胞中也发挥了关键作用。 尽管之前的研究已经解析了 LAT1-4F2hc 复合物与抑制剂结合的结构，并对 LAT1 的功能进行了分析，但对于该复合物的转运机制仍存在许多未解之谜。
在本篇论文中，我们利用冷冻电镜技术，解析了 LAT1-4F2hc 复合物与底物酪氨酸、色氨酸、左旋多巴和亮氨酸结合状态下的结构，分辨率分别为 3.2 Å、 3.57 Å、 3.56 Å 和 3.1 Å。 通过对这些结构进行分析，我们发现LAT1 在朝向胞外开口的构象状态中存在一系列中间态，并且观察到 LAT1与底物结合模式受到底物侧链的影响。 同时， 结合生化实验，我们也发现了关键氨基酸 Tyr259 和 Phe400 的突变会抑制 LAT1 的转运能力。这些发现为深入理解 LAT1 的结构与功能提供了重要线索。最后，我们在前人的研究基础上，进一步完善了 LAT1-4F2hc 复合物的转运机制模型。这一模型的建立将有助于我们更全面地理解氨基酸转运的分子机制，为未来设计更有效的药物治疗方案提供有力支持。

Amino acids are integral to maintaining essential biological functions. Beyond their role in protein synthesis, they are key participants in critical biological processes including metabolism, signal transduction, and cellular structure maintenance. Dysregulation of amino acid metabolism frequently underlies the onset of diverse diseases, such as phenylketonuria, Parkinson's disease, and cancer. In the process of amino acid transport, the transporter protein LAT1 (SLC7A5), in conjunction with its partner protein 4F2hc (SLC3A2), forms a vital heterodimeric complex. Recent studies have highlighted LAT1's pivotal role not only in diseases like cancer, obesity, and diabetes where its expression is dysregulated, but also in various active immune cells. While structural elucidation of the LAT1-4F2hc complex and functional analysis of LAT1 have been conducted in previous research, significant mysteries persist regarding the transport mechanism of this complex.
In this study, employing cryo-electron microscopy, we elucidated the structures of the LAT1-4F2hc complex bound to substrates including tyrosine, tryptophan, levodopa, and leucine, at resolutions of 3.2 Å, 3.57 Å, 3.56 Å, and 3.1 Å respectively. Analysis of these structures revealed a series of intermediate states of LAT1 in a conformation facing the extracellular side, with substrate binding mode influenced by substrate side chains. Additionally, biochemical experiments highlighted the inhibitory effect on LAT1 transport capability upon mutation of key amino acids Tyr259 and Phe400. These findings provide crucial insights into the structure and function of LAT1. Furthermore, building upon previous research, we refined the transport mechanism model of the LAT1-4F2hc complex. This model contributes to a comprehensive understanding of the molecular mechanism underlying amino acid transport and provides a solid foundation for designing more effective drug therapies in the future.

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