Structure and mechanism of human cystine exporter cystinosin.
Structure and mechanism of human cystine exporter cystinosin.
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人胱氨酸出口商cystinosin的结构和机制。
DOI：
10.1016/j.cell.2022.08.020
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发表时间：
2022-09-29
期刊：
影响因子：
64.5
通讯作者：
Li, Xiaochun
中科院分区：
文献类型：
--
作者：
Guo, Xue;Schmiege, Philip;Assafa, Tufa E.;Wang, Rong;Xu, Yan;Donnelly, Linda;Fine, Michael;Ni, Xiaodan;Jiang, Jiansen;Millhauser, Glenn;Feng, Liang;Li, Xiaochun
Lysosomal amino acid efflux by proton-driven transporters is essential for lysosomal homeostasis, amino acid recycling, mTOR signaling, and maintaining lysosomal pH. To unravel mechanisms of these transporters, we focus on cystinosin, a prototypical lysosomal amino acid transporter that exports cystine to the cytosol, where its reduction to cysteine supplies this limiting amino acid for diverse fundamental processes and controlling nutrient adaptation. Cystinosin mutations cause cystinosis, a devastating lysosomal storage disease. Here, we present structures of human cystinosin in lumen-open, cytosol-open, and cysteine-bound states, which uncover the cystine recognition mechanism and capture key conformational states of the transport cycle. Our structures, along with functional studies and Double Electron–Electron Resonance spectroscopic investigations, reveal the molecular basis for the transporter’s conformational transitions and protonation switch, show conformation-dependent Ragulator-Rag complex engagement, and demonstrate an unexpected activation mechanism. These findings provide molecular insights into lysosomal amino acid efflux and a potential therapeutic strategy. Structural and biophysical studies of human cystinosin reveal molecular mechanisms and conformational dynamics in proton-coupled lysosomal amino acid transport.
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脂质体中膜蛋白取向的快速估计。
影响因子：
3.2
作者：
Deutschmann, Sabina;Rimle, Lukas;von Ballmoos, Christoph
通讯作者：
von Ballmoos, Christoph
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
14.8
作者：
通讯作者：
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影响因子：
14.8
作者：
通讯作者：
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