8dyp
From Proteopedia
Crystal structure of human cystine transporter cystinosin
Structural highlights
DiseaseCTNS_HUMAN Juvenile nephropathic cystinosis;Ocular cystinosis;Infantile nephropathic cystinosis. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionCTNS_HUMAN Cystine/H(+) symporter that mediates export of cystine, the oxidized dimer of cysteine, from lysosomes (PubMed:11689434, PubMed:18337546, PubMed:22232659, PubMed:29467429, PubMed:33208952, PubMed:15128704). Plays an important role in melanin synthesis by catalyzing cystine export from melanosomes, possibly by inhibiting pheomelanin synthesis (PubMed:22649030). In addition to cystine export, also acts as a positive regulator of mTORC1 signaling in kidney proximal tubular cells, via interactions with components of the v-ATPase and Ragulator complexes (By similarity). Also involved in small GTPase-regulated vesicle trafficking and lysosomal localization of LAMP2A, independently of cystine transporter activity (By similarity).[UniProtKB:P57757][1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedLysosomal amino acid efflux by proton-driven transporters is essential for lysosomal homeostasis, amino acid recycling, mTOR signaling, and maintaining lysosomal pH. To unravel the 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 cystine-bound states, which uncover the cystine recognition mechanism and capture the 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. Structure and mechanism of human cystine exporter cystinosin.,Guo X, Schmiege P, Assafa TE, Wang R, Xu Y, Donnelly L, Fine M, Ni X, Jiang J, Millhauser G, Feng L, Li X Cell. 2022 Sep 29;185(20):3739-3752.e18. doi: 10.1016/j.cell.2022.08.020. Epub, 2022 Sep 15. PMID:36113465[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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