Amino acid transporters play a key role controlling the flow of nutrients across the lysosomal membrane and regulating metabolism in the cell. Mutations in the gene encoding the transporter cystinosin result in cystinosis, an autosomal recessive metabolic disorder characterised by the accumulation of cystine crystals in the lysosome. Cystinosin is a member of the PQ-loop family of solute carrier (SLC) transporters and uses the proton gradient to drive cystine export into the cytoplasm. However, the molecular basis for cystinosin function remains elusive, hampering efforts to develop novel treatments for cystinosis and understand the mechanisms of ion driven transport in the PQ-loop family. To address these questions, we present the crystal structures of cystinosin from Arabidopsis thaliana in both apo and cystine bound states. Using a combination of in vitro and in vivo based assays, we establish a mechanism for cystine recognition and proton coupled transport. Mutational mapping and functional characterisation of human cystinosin further provide a framework for understanding the molecular impact of disease-causing mutations.

氨基酸转运蛋白在控制营养物质通过溶酶体膜的流动和调节细胞内的新陈代谢方面发挥着关键作用。编码转运蛋白胱氨酸蛋白酶的基因突变导致胱氨酸病，这是一种常染色体隐性遗传代谢疾病，其特征在于溶酶体中胱氨酸晶体的积累。Cystinosin 是溶质载体 (SLC) 转运蛋白的 PQ 环家族的成员，它使用质子梯度来驱动胱氨酸输出到细胞质中。然而，胱氨酸功能的分子基础仍然难以捉摸，阻碍了开发新的胱氨酸病治疗方法和了解 PQ 环家族中离子驱动转运机制的努力。为了解决这些问题，我们提出了拟南芥胱氨酸的晶体结构在载脂蛋白和胱氨酸结合状态。结合体外和体内试验，我们建立了胱氨酸识别和质子耦合转运的机制。人类胱氨酸的突变作图和功能表征进一步为了解致病突变的分子影响提供了一个框架。