美国德克萨斯大学Xiaochun Li等研究人员合作揭示人类胱氨酸输出蛋白cystinosin的结构和机制。相关论文于2022年9月15日发表在《细胞》杂志上。

研究人员表示，由质子驱动的转运体排出的溶酶体氨基酸对于溶酶体的平衡、氨基酸循环、mTOR信号传导和维持溶酶体的pH值至关重要。

为了揭示这些转运体的机制，研究人员重点关注了cystinosin，这是一种典型的溶酶体氨基酸转运体，它将胱氨酸输出到细胞膜，进而被还原成半胱氨酸，为不同的基本过程和控制营养适应提供这种限制性氨基酸。cystinosin突变导致胱氨酸病，这是一种毁灭性的溶酶体储存疾病。研究人员报道了人类cystinosin在腔体开放、细胞膜开放和胱氨酸结合状态下的结构，这些结构揭示了胱氨酸的识别机制，并捕捉到运输周期的关键构象状态。

这些结构连同功能研究和双电子共振光谱研究揭示了转运体的构象转换和质子化开关的分子基础，显示了构象依赖的Ragulator-Rag复合物的参与，并展示了一个意想不到的激活机制。这些发现提供了对溶酶体氨基酸外流的分子见解和一种潜在的治疗策略。

附：英文原文

Title: Structure and mechanism of human cystine exporter cystinosin

Author: Xue Guo, Philip Schmiege, Tufa E. Assafa, Rong Wang, Yan Xu, Linda Donnelly, Michael Fine, Xiaodan Ni, Jiansen Jiang, Glenn Millhauser, Liang Feng, Xiaochun Li

Issue&Volume: 2022-09-15

Abstract: Lysosomal amino acid efflux by proton-driven transporters is essential for lysosomalhomeostasis, amino acid recycling, mTOR signaling, and maintaining lysosomal pH. Tounravel the mechanisms of these transporters, we focus on cystinosin, a prototypicallysosomal amino acid transporter that exports cystine to the cytosol, where its reductionto cysteine supplies this limiting amino acid for diverse fundamental processes andcontrolling nutrient adaptation. Cystinosin mutations cause cystinosis, a devastatinglysosomal storage disease. Here, we present structures of human cystinosin in lumen-open,cytosol-open, and cystine-bound states, which uncover the cystine recognition mechanismand capture the key conformational states of the transport cycle. Our structures,along with functional studies and double electron-electron resonance spectroscopicinvestigations, reveal the molecular basis for the transporter’s conformational transitionsand protonation switch, show conformation-dependent Ragulator-Rag complex engagement,and demonstrate an unexpected activation mechanism. These findings provide molecularinsights into lysosomal amino acid efflux and a potential therapeutic strategy.

DOI: 10.1016/j.cell.2022.08.020

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01114-X