8dyp

From Proteopedia

(Difference between revisions)

Revision as of 17:32, 18 October 2023

Crystal structure of human cystine transporter cystinosin

Structural highlights

8dyp is a 2 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.4Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CTNS_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.

Function

CTNS_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 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^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Kalatzis V, Cherqui S, Antignac C, Gasnier B. Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter. EMBO J. 2001 Nov 1;20(21):5940-9. doi: 10.1093/emboj/20.21.5940. PMID:11689434 doi:http://dx.doi.org/10.1093/emboj/20.21.5940
↑ Kalatzis V, Nevo N, Cherqui S, Gasnier B, Antignac C. Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin. Hum Mol Genet. 2004 Jul 1;13(13):1361-71. doi: 10.1093/hmg/ddh152. Epub 2004 May , 5. PMID:15128704 doi:http://dx.doi.org/10.1093/hmg/ddh152
↑ Taranta A, Petrini S, Palma A, Mannucci L, Wilmer MJ, De Luca V, Diomedi-Camassei F, Corallini S, Bellomo F, van den Heuvel LP, Levtchenko EN, Emma F. Identification and subcellular localization of a new cystinosin isoform. Am J Physiol Renal Physiol. 2008 May;294(5):F1101-8. doi:, 10.1152/ajprenal.00413.2007. Epub 2008 Mar 12. PMID:18337546 doi:http://dx.doi.org/10.1152/ajprenal.00413.2007
↑ Ruivo R, Bellenchi GC, Chen X, Zifarelli G, Sagne C, Debacker C, Pusch M, Supplisson S, Gasnier B. Mechanism of proton/substrate coupling in the heptahelical lysosomal transporter cystinosin. Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):E210-7. doi:, 10.1073/pnas.1115581109. Epub 2012 Jan 9. PMID:22232659 doi:http://dx.doi.org/10.1073/pnas.1115581109
↑ Chiaverini C, Sillard L, Flori E, Ito S, Briganti S, Wakamatsu K, Fontas E, Berard E, Cailliez M, Cochat P, Foulard M, Guest G, Niaudet P, Picardo M, Bernard FX, Antignac C, Ortonne JP, Ballotti R. Cystinosin is a melanosomal protein that regulates melanin synthesis. FASEB J. 2012 Sep;26(9):3779-89. doi: 10.1096/fj.11-201376. Epub 2012 May 30. PMID:22649030 doi:http://dx.doi.org/10.1096/fj.11-201376
↑ Deshpande AA, Shukla A, Bachhawat AK. A Genetic Screen for Investigating the Human Lysosomal CystineTransporter, Cystinosin. Sci Rep. 2018 Feb 21;8(1):3442. doi: 10.1038/s41598-018-21483-x. PMID:29467429 doi:http://dx.doi.org/10.1038/s41598-018-21483-x
↑ Adelmann CH, Traunbauer AK, Chen B, Condon KJ, Chan SH, Kunchok T, Lewis CA, Sabatini DM. MFSD12 mediates the import of cysteine into melanosomes and lysosomes. Nature. 2020 Dec;588(7839):699-704. doi: 10.1038/s41586-020-2937-x. Epub 2020 Nov, 18. PMID:33208952 doi:http://dx.doi.org/10.1038/s41586-020-2937-x
↑ Guo X, Schmiege P, Assafa TE, Wang R, Xu Y, Donnelly L, Fine M, Ni X, Jiang J, Millhauser G, Feng L, Li X. Structure and mechanism of human cystine exporter cystinosin. Cell. 2022 Sep 29;185(20):3739-3752.e18. doi: 10.1016/j.cell.2022.08.020. Epub, 2022 Sep 15. PMID:36113465 doi:http://dx.doi.org/10.1016/j.cell.2022.08.020

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8dyp"

Categories: Homo sapiens | Large Structures | Synthetic construct | Feng L | Guo X

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[8dyp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DYP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DYP FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.4&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=8dyp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dyp OCA], [https://pdbe.org/8dyp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dyp RCSB], [https://www.ebi.ac.uk/pdbsum/8dyp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dyp ProSAT]</span></td></tr>
 </table>

8dyp

From Proteopedia

Revision as of 17:32, 18 October 2023

Crystal structure of human cystine transporter cystinosin

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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