异源多聚体氨基酸转运蛋白结构与功能研究

异源多聚体氨基酸转运蛋白(HAT)是一类由属于SLC7家族的轻链蛋白以及属于SLC3家族的重链蛋白组成的异源二聚体分子。轻链蛋白具有转运底物的功能。重链蛋白对轻链蛋白的细胞内定位和运输有作用。SLC3和SLC7家族都隶属于更大的APC超家族。绝大部分的HAT是双向交换转运蛋白，介导多种氨基酸、激素以及药物分子的跨膜转运。HAT与细胞增殖，血管生成，肿瘤、癌症的发生、发展密切相关。HAT转运蛋白的功能障碍还与多种代谢遗传疾病有关。了解HAT的结构和工作机制对基础科学研究和药物开发都非常重要。本研究计划拟利用单颗粒冷冻电镜技术解析多种HAT转运蛋白的结构，以及HAT转运蛋白处于不同构象、不同状态的结构，在此基础上结合生化功能实验、定点突变等技术手段阐明HAT识别底物的机制以及跨膜转运机制。

Heteromeric amino acid transporters (HAT) are heterodimer molecules composed of light chain proteins belonging to the SLC7 family and heavy chain proteins belonging to the SLC3 family. Light chain proteins catalyze transporting of substrates. Heavy chain proteins play an essential role in cellular localization and traffic of the light chain proteins. The SLC3 and SLC7 families belong to the larger APC (Amino acids, Polyamines and organoCations) superfamily. Most of the HATs are exchanger, which mediate the transmembrane transport of many amino acids, hormones and drug molecules. HATs are closely related to cell proliferation, angiogenesis, tumorigenesis and development of cancer. The dysfunction of HAT transporters is also associated with a variety of metabolic genetic diseases. Understanding the structure and working mechanism of HATs is very important for both basic scientific research and drug development. This proposal intends to solve several structures of HAT transporters with single particle cryo EM, in different conformations and different states. Based on structures, the mechanisms of substrate recognition and transmembrane transport will be further investigated by means of biochemical experiments and site-directed mutagenesis.