View source for 8dkx


==Cryo-EM structure of cystinosin N288K mutant in a cytosol-open state at pH7.5==
<StructureSection load='8dkx' size='340' side='right'caption='[[8dkx]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8dkx]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DKX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DKX FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8dkx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dkx OCA], [https://pdbe.org/8dkx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dkx RCSB], [https://www.ebi.ac.uk/pdbsum/8dkx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dkx ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CTNS_HUMAN 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 ==
[https://www.uniprot.org/uniprot/CTNS_HUMAN 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]<ref>PMID:11689434</ref> <ref>PMID:15128704</ref> <ref>PMID:18337546</ref> <ref>PMID:22232659</ref> <ref>PMID:22649030</ref> <ref>PMID:29467429</ref> <ref>PMID:33208952</ref> <ref>PMID:36113465</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:36113465</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8dkx" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Li X]]
[[Category: Schmiege P]]