8dkm | pdb_00008dkm

Cryo-EM structure of cystine-bound cystinosin in a lumen-open state

spinqualitylabelsall models 8dkm, resolution 3.39Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8dkm is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.39Å Ligands: IYY Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CTNS_HUMAN Ocular cystinosis;Juvenile nephropathic 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. Function CTNS_HUMAN Cystine/H(+) symporter that mediates export of cystine, the oxidized dimer of cysteine, from lysosomes (PubMed:11689434, PubMed:15128704, PubMed:18337546, PubMed:22232659, PubMed:29467429, PubMed:33208952, PubMed:36113465). 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 (PubMed:36113465). Also involved in small GTPase-regulated vesicle trafficking and lysosomal localization of LAMP2A, independently of cystine transporter activity (By similarity).[UniProtKB:P57757] Publication Abstract from PubMed Lysosomal 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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