ID CTNS_HUMAN Reviewed; 367 AA. AC O60931; D3DTJ5; Q8IZ01; Q9UNK6; DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot. DT 24-NOV-2009, sequence version 2. DT 27-MAR-2024, entry version 182. DE RecName: Full=Cystinosin {ECO:0000303|PubMed:9537412}; DE Flags: Precursor; GN Name=CTNS {ECO:0000303|PubMed:9537412, ECO:0000312|HGNC:HGNC:2518}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), AND VARIANT ILE-260. RC TISSUE=Kidney; RX PubMed=9537412; DOI=10.1038/ng0498-319; RA Town M., Jean G., Cherqui S., Attard M., Forestier L., Whitmore S.A., RA Callen D.F., Gribouval O., Broyer M., Bates G.P., van 't Hoff W., RA Antignac C.; RT "A novel gene encoding an integral membrane protein is mutated in RT nephropathic cystinosis."; RL Nat. Genet. 18:319-324(1998). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ILE-260. RX PubMed=10673275; DOI=10.1101/gr.10.2.165; RA Touchman J.W., Anikster Y., Dietrich N.L., Maduro V.V.B., McDowell G., RA Shotelersuk V., Bouffard G.G., Beckstrom-Sternberg S.M., Gahl W.A., RA Green E.D.; RT "The genomic region encompassing the nephropathic cystinosis gene (CTNS): RT complete sequencing of a 200-kb segment and discovery of a novel gene RT within the common cystinosis-causing deletion."; RL Genome Res. 10:165-173(2000). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT ILE-260. RC TISSUE=Spleen; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16625196; DOI=10.1038/nature04689; RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.; RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the RT human lineage."; RL Nature 440:1045-1049(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT ILE-260. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT ILE-260. RC TISSUE=Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 228-367, AND VARIANT ILE-260. RX PubMed=10068513; DOI=10.1006/mgme.1998.2790; RA Anikster Y., Lucero C., Touchman J.W., Huizing M., McDowell G., RA Shotelersuk V., Green E.D., Gahl W.A.; RT "Identification and detection of the common 65-kb deletion breakpoint in RT the nephropathic cystinosis gene (CTNS)."; RL Mol. Genet. Metab. 66:111-116(1999). RN [8] RP PROTEIN SEQUENCE OF 23-33, SUBCELLULAR LOCATION, GLYCOSYLATION AT ASN-36; RP ASN-41; ASN-51; ASN-66; ASN-84; ASN-104 AND ASN-107, CHARACTERIZATION OF RP VARIANT CTNSJAN 67-ILE--PRO-73 DEL, AND MUTAGENESIS OF ASN-66. RX PubMed=28082515; DOI=10.1074/mcp.m116.063867; RA Nevo N., Thomas L., Chhuon C., Andrzejewska Z., Lipecka J., Guillonneau F., RA Bailleux A., Edelman A., Antignac C., Guerrera I.C.; RT "Impact of cystinosin glycosylation on protein stability by differential RT dynamic stable isotope labeling by amino acids in cell culture (SILAC)."; RL Mol. Cell. Proteomics 16:457-468(2017). RN [9] RP REVIEW ON VARIANTS CYSTINOSIS. RX PubMed=10571941; RX DOI=10.1002/(sici)1098-1004(199912)14:6<454::aid-humu2>3.0.co;2-h; RA Anikster Y., Shotelersuk V., Gahl W.A.; RT "CTNS mutations in patients with cystinosis."; RL Hum. Mutat. 14:454-458(1999). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR RP LOCATION, AND CHARACTERIZATION OF VARIANT CTNS ARG-308. RX PubMed=11689434; DOI=10.1093/emboj/20.21.5940; RA Kalatzis V., Cherqui S., Antignac C., Gasnier B.; RT "Cystinosin, the protein defective in cystinosis, is a H(+)-driven RT lysosomal cystine transporter."; RL EMBO J. 20:5940-5949(2001). RN [11] RP SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF 280-LYS--ASN-288; RP 281-TYR--GLN-284; 286-TYR--PHE-289; 289-PHE--SER-298; 362-GLY--LEU-366; RP GLY-362; TYR-363; ASP-364; GLN-365 AND LEU-366. RX PubMed=11150305; DOI=10.1074/jbc.m010562200; RA Cherqui S., Kalatzis V., Trugnan G., Antignac C.; RT "The targeting of cystinosin to the lysosomal membrane requires a tyrosine- RT based signal and a novel sorting motif."; RL J. Biol. Chem. 276:13314-13321(2001). RN [12] RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS]. RC TISSUE=Placenta; RX PubMed=17897319; DOI=10.1111/j.1600-0854.2007.00643.x; RA Schroeder B., Wrocklage C., Pan C., Jaeger R., Koesters B., Schaefer H., RA Elsaesser H.-P., Mann M., Hasilik A.; RT "Integral and associated lysosomal membrane proteins."; RL Traffic 8:1676-1686(2007). RN [13] RP FUNCTION, SUBCELLULAR LOCATION (ISOFORM 2), CATALYTIC ACTIVITY (ISOFORM 2), RP AND ALTERNATIVE SPLICING. RX PubMed=18337546; DOI=10.1152/ajprenal.00413.2007; RA Taranta A., Petrini S., Palma A., Mannucci L., Wilmer M.J., De Luca V., RA Diomedi-Camassei F., Corallini S., Bellomo F., van den Heuvel L.P., RA Levtchenko E.N., Emma F.; RT "Identification and subcellular localization of a new cystinosin isoform."; RL Am. J. Physiol. 294:F1101-F1108(2008). RN [14] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=22649030; DOI=10.1096/fj.11-201376; RA Chiaverini C., Sillard L., Flori E., Ito S., Briganti S., Wakamatsu K., RA Fontas E., Berard E., Cailliez M., Cochat P., Foulard M., Guest G., RA Niaudet P., Picardo M., Bernard F.X., Antignac C., Ortonne J.P., RA Ballotti R.; RT "Cystinosin is a melanosomal protein that regulates melanin synthesis."; RL FASEB J. 26:3779-3789(2012). RN [15] RP TISSUE SPECIFICITY (ISOFORMS 1 AND 2). RX PubMed=22544350; DOI=10.1007/s00418-012-0958-8; RA Taranta A., Petrini S., Citti A., Boldrini R., Corallini S., Bellomo F., RA Levtchenko E., Emma F.; RT "Distribution of cystinosin-LKG in human tissues."; RL Histochem. Cell Biol. 138:351-363(2012). RN [16] RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SITE, RP CHARACTERIZATION OF VARIANT CTNS ARG-308, AND MUTAGENESIS OF TYR-143; RP ARG-152; ASP-161; ASP-205; HIS-211; TYR-281; ASP-305 AND LYS-335. RX PubMed=22232659; DOI=10.1073/pnas.1115581109; RA Ruivo R., Bellenchi G.C., Chen X., Zifarelli G., Sagne C., Debacker C., RA Pusch M., Supplisson S., Gasnier B.; RT "Mechanism of proton/substrate coupling in the heptahelical lysosomal RT transporter cystinosin."; RL Proc. Natl. Acad. Sci. U.S.A. 109:E210-E217(2012). RN [17] RP SUBCELLULAR LOCATION, AND INTERACTION WITH AP-3 COMPLEX (ISOFORM 1). RX PubMed=25753619; DOI=10.1111/tra.12277; RA Andrzejewska Z., Nevo N., Thomas L., Bailleux A., Chauvet V., Benmerah A., RA Antignac C.; RT "Lysosomal targeting of cystinosin requires AP-3."; RL Traffic 16:712-726(2015). RN [18] RP SUBCELLULAR LOCATION (ISOFORM 2). RX PubMed=27148969; DOI=10.1371/journal.pone.0154805; RA Bellomo F., Taranta A., Petrini S., Venditti R., Rocchetti M.T., Rega L.R., RA Corallini S., Gesualdo L., De Matteis M.A., Emma F.; RT "Carboxyl-terminal SSLKG motif of the human cystinosin-LKG plays an RT important role in plasma membrane sorting."; RL PLoS ONE 11:e0154805-e0154805(2016). RN [19] RP FUNCTION, AND MUTAGENESIS OF GLY-131; ALA-137; SER-270; LEU-274; GLY-309; RP SER-312; 362-GLY--LEU-366; TYR-363 AND LEU-366. RX PubMed=29467429; DOI=10.1038/s41598-018-21483-x; RA Deshpande A.A., Shukla A., Bachhawat A.K.; RT "A genetic screen for investigating the human lysosomal cystine RT transporter, cystinosin."; RL Sci. Rep. 8:3442-3442(2018). RN [20] RP FUNCTION. RX PubMed=33208952; DOI=10.1038/s41586-020-2937-x; RA Adelmann C.H., Traunbauer A.K., Chen B., Condon K.J., Chan S.H., RA Kunchok T., Lewis C.A., Sabatini D.M.; RT "MFSD12 mediates the import of cysteine into melanosomes and lysosomes."; RL Nature 588:699-704(2020). RN [21] {ECO:0007744|PDB:8DKE, ECO:0007744|PDB:8DKI, ECO:0007744|PDB:8DKM, ECO:0007744|PDB:8DKW, ECO:0007744|PDB:8DKX, ECO:0007744|PDB:8DYP} RP STRUCTURE BY ELECTRON MICROSCOPY (3.00 ANGSTROMS) OF 1-362 IN COMPLEX WITH RP CYSTINE, FUNCTION, ACTIVITY REGULATION, TRANSPORTER ACTIVITY, AND RP MUTAGENESIS OF TYR-134; TRP-138; PHE-142; GLN-145; ASN-166; PHE-170; RP ASP-205; LYS-273; LYS-280; TYR-281; GLN-284; ASN-301; ASP-305; GLN-319; RP LYS-335 AND ASP-346. RX PubMed=36113465; DOI=10.1016/j.cell.2022.08.020; RA Guo X., Schmiege P., Assafa T.E., Wang R., Xu Y., Donnelly L., Fine M., RA Ni X., Jiang J., Millhauser G., Feng L., Li X.; RT "Structure and mechanism of human cystine exporter cystinosin."; RL Cell 185:3739-3752(2022). RN [22] RP VARIANTS CTNS ASP-169; ARG-182; ASN-205; ASP-205 DEL; ASN-298; GLY-305; RP ARG-308 AND ARG-339, VARIANT CTNSJAN 67-ILE--PRO-73 DEL, AND VARIANT RP ARG-292. RX PubMed=9792862; DOI=10.1086/302118; RA Shotelersuk V., Larson D., Anikster Y., McDowell G., Lemons R., RA Bernardini I., Guo J., Thoene J., Gahl W.A.; RT "CTNS mutations in an American-based population of cystinosis patients."; RL Am. J. Hum. Genet. 63:1352-1362(1998). RN [23] RP VARIANTS CTNS PHE-133 AND PRO-158. RX PubMed=10482956; DOI=10.1038/sj.ejhg.5200349; RA McGowan-Jordan J., Stoddard K., Podolsky L., Orrbine E., McLaine P., RA Town M., Goodyer P., MacKenzie A., Heick H.; RT "Molecular analysis of cystinosis: probable Irish origin of the most common RT French Canadian mutation."; RL Eur. J. Hum. Genet. 7:671-678(1999). RN [24] RP VARIANTS CTNSJAN ARG-280 AND LYS-323. RX PubMed=10444339; DOI=10.1006/mgme.1999.2876; RA Thoene J., Lemons R., Anikster Y., Mullet J., Paelicke K., Lucero C., RA Gahl W.A., Schneider J., Shu S.G., Campbell H.T.; RT "Mutations of CTNS causing intermediate cystinosis."; RL Mol. Genet. Metab. 67:283-293(1999). RN [25] RP VARIANTS CTNS PHE-139; ASP-205 DEL; SER-270 DEL; TYR-305; ARG-308; PRO-338; RP ARG-339; 343-ILE--ASP-346 DEL AND ASN-346, VARIANT ILE-42, AND VARIANT RP CTNSJAN PRO-CYS-SER-154 INS. RX PubMed=10556299; DOI=10.1093/hmg/8.13.2507; RA Attard M., Jean G., Forestier L., Cherqui S., van 't Hoff W., Broyer M., RA Antignac C., Town M.; RT "Severity of phenotype in cystinosis varies with mutations in the CTNS RT gene: predicted effect on the model of cystinosin."; RL Hum. Mol. Genet. 8:2507-2514(1999). RN [26] RP VARIANT CTNSANN ARG-197. RX PubMed=10625078; DOI=10.1203/00006450-200001000-00007; RA Anikster Y., Lucero C., Guo J., Huizing M., Shotelersuk V., Bernardini I., RA McDowell G., Iwata F., Kaiser-Kupfer M.I., Jaffe R., Thoene J., RA Schneider J.A., Gahl W.A.; RT "Ocular nonnephropathic cystinosis: clinical, biochemical, and molecular RT correlations."; RL Pediatr. Res. 47:17-23(2000). RN [27] RP VARIANTS CTNS VAL-308 AND ARG-339. RX PubMed=12204010; DOI=10.1002/humu.9063; RA Kiehntopf M., Schickel J., Gonne B., Koch H.G., Superti-Furga A., RA Steinmann B., Deufel T., Harms E.; RT "Analysis of the CTNS gene in patients of German and Swiss origin with RT nephropathic cystinosis."; RL Hum. Mutat. 20:237-237(2002). RN [28] RP VARIANTS CTNS VAL-110; ARG-222; LYS-288; 346-ASP--PHE-349 DEL AND RP ASP-VAL-GLU-PHE-349 INS, AND VARIANTS CTNSJAN THR-177 AND LEU-200. RX PubMed=12442267; DOI=10.1002/humu.10141; RA Kalatzis V., Cohen-Solal L., Cordier B., Frishberg Y., Kemper M., RA Nuutinen E.M., Legrand E., Cochat P., Antignac C.; RT "Identification of 14 novel CTNS mutations and characterization of seven RT splice site mutations associated with cystinosis."; RL Hum. Mutat. 20:439-446(2002). RN [29] RP VARIANTS CTNS ILE-287; ARG-308; ARG-337 AND ARG-339, AND VARIANT ILE-260. RX PubMed=12825071; DOI=10.1038/sj.ejhg.5200993; RA Mason S., Pepe G., Dall'Amico R., Tartaglia S., Casciani S., Greco M., RA Bencivenga P., Murer L., Rizzoni G., Tenconi R., Clementi M.; RT "Mutational spectrum of the CTNS gene in Italy."; RL Eur. J. Hum. Genet. 11:503-508(2003). RN [30] RP FUNCTION, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS CTNS VAL-110; RP PHE-133; PHE-139; PHE-141; PRO-158; ASP-169; SER-177; ARG-182; ASN-205; RP ASP-205 DEL; ARG-222; SER-270 DEL; LYS-288; ASN-298; TYR-305; ARG-308; RP PRO-338; ARG-339; 343-ILE--ASP-346 DEL; ASP-346--349-PHE DEL AND RP ASP-VAL-GLU-PHE-349 INS, CHARACTERIZATION OF VARIANT CTNSJAN 67-ILE--PRO-73 RP DEL; PRO-CYS-SER-154 INS; LEU-200; ARG-280; LYS-323 AND ASN-346, RP CHARACTERIZATION OF VARIANT CTNSANN ARG-197, AND CHARACTERIZATION OF RP VARIANT ILE-42 AND ILE-260. RX PubMed=15128704; DOI=10.1093/hmg/ddh152; RA Kalatzis V., Nevo N., Cherqui S., Gasnier B., Antignac C.; RT "Molecular pathogenesis of cystinosis: effect of CTNS mutations on the RT transport activity and subcellular localization of cystinosin."; RL Hum. Mol. Genet. 13:1361-1371(2004). RN [31] RP VARIANTS CTNS SER-177 AND ARG-338. RX PubMed=19852576; DOI=10.3109/13816810903200953; RA Aldahmesh M.A., Humeidan A., Almojalli H.A., Khan A.O., Rajab M., RA Al-Abbad A.A., Meyer B.F., Alkuraya F.S.; RT "Characterization of CTNS mutations in Arab patients with cystinosis."; RL Ophthalmic Genet. 30:185-189(2009). RN [32] RP VARIANTS CTNS ASP-309 AND LYS-323. RX PubMed=22450360; DOI=10.1016/j.gene.2012.03.047; RA Yeetong P., Tongkobpetch S., Kingwatanakul P., Deekajorndech T., RA Bernardini I.M., Suphapeetiporn K., Gahl W.A., Shotelersuk V.; RT "Two novel CTNS mutations in cystinosis patients in Thailand."; RL Gene 499:323-325(2012). RN [33] RP VARIANTS CTNS GLY-151; ASP-157 AND CYS-173. RX PubMed=21786142; DOI=10.1007/s00467-011-1942-6; RA Topaloglu R., Vilboux T., Coskun T., Ozaltin F., Tinloy B., Gunay-Aygun M., RA Bakkaloglu A., Besbas N., van den Heuvel L., Kleta R., Gahl W.A.; RT "Genetic basis of cystinosis in Turkish patients: a single-center RT experience."; RL Pediatr. Nephrol. 27:115-121(2012). CC -!- FUNCTION: Cystine/H(+) symporter that mediates export of cystine, the CC oxidized dimer of cysteine, from lysosomes (PubMed:11689434, CC PubMed:18337546, PubMed:22232659, PubMed:29467429, PubMed:33208952, CC PubMed:15128704, PubMed:36113465). Plays an important role in melanin CC synthesis by catalyzing cystine export from melanosomes, possibly by CC inhibiting pheomelanin synthesis (PubMed:22649030). In addition to CC cystine export, also acts as a positive regulator of mTORC1 signaling CC in kidney proximal tubular cells, via interactions with components of CC the v-ATPase and Ragulator complexes (PubMed:36113465). Also involved CC in small GTPase-regulated vesicle trafficking and lysosomal CC localization of LAMP2A, independently of cystine transporter activity CC (By similarity). {ECO:0000250|UniProtKB:P57757, CC ECO:0000269|PubMed:11689434, ECO:0000269|PubMed:15128704, CC ECO:0000269|PubMed:18337546, ECO:0000269|PubMed:22232659, CC ECO:0000269|PubMed:22649030, ECO:0000269|PubMed:29467429, CC ECO:0000269|PubMed:33208952, ECO:0000269|PubMed:36113465}. CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+)(out) + L-cystine(out) = H(+)(in) + L-cystine(in); CC Xref=Rhea:RHEA:66172, ChEBI:CHEBI:15378, ChEBI:CHEBI:35491; CC Evidence={ECO:0000269|PubMed:11689434, ECO:0000269|PubMed:22232659, CC ECO:0000269|PubMed:36113465}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66173; CC Evidence={ECO:0000269|PubMed:11689434, ECO:0000269|PubMed:22232659, CC ECO:0000269|PubMed:36113465}; CC -!- CATALYTIC ACTIVITY: [Isoform 1]: CC Reaction=H(+)(out) + L-cystine(out) = H(+)(in) + L-cystine(in); CC Xref=Rhea:RHEA:66172, ChEBI:CHEBI:15378, ChEBI:CHEBI:35491; CC Evidence={ECO:0000269|PubMed:18337546}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66173; CC Evidence={ECO:0000269|PubMed:18337546}; CC -!- CATALYTIC ACTIVITY: [Isoform 2]: CC Reaction=H(+)(out) + L-cystine(out) = H(+)(in) + L-cystine(in); CC Xref=Rhea:RHEA:66172, ChEBI:CHEBI:15378, ChEBI:CHEBI:35491; CC Evidence={ECO:0000269|PubMed:18337546}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66173; CC Evidence={ECO:0000269|PubMed:18337546}; CC -!- ACTIVITY REGULATION: Switches between a lumen- and a cytosol-open CC conformation: pH induces conformational changes and shifts the CC equilibrium to facilitate the transition between the lumen- and CC cytosol-open conformation, thereby promoting cystine transport CC (PubMed:36113465). Protonation of specific aspartate residues (Asp-205, CC Asp-305 and Asp-346) favors the cytosol-open conformation CC (PubMed:36113465). {ECO:0000269|PubMed:36113465}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=75 uM for cystine (at pH 5.0) {ECO:0000269|PubMed:22232659}; CC KM=278 uM for cystine {ECO:0000269|PubMed:11689434}; CC -!- SUBUNIT: Interacts with components of the V-ATPase complex (By CC similarity). Interacts with components of the Ragulator complex CC (PubMed:36113465). Interacts with RRAGA/RagA and RRAGC/RagC (By CC similarity). Interacts with AP-3 complex subunit mu (AP3M1 or AP3M2) CC (PubMed:25753619). {ECO:0000250|UniProtKB:P57757, CC ECO:0000269|PubMed:25753619, ECO:0000269|PubMed:36113465}. CC -!- INTERACTION: CC O60931-2; Q14749: GNMT; NbExp=3; IntAct=EBI-19888994, EBI-744239; CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Lysosome membrane CC {ECO:0000269|PubMed:11150305, ECO:0000269|PubMed:11689434, CC ECO:0000269|PubMed:15128704, ECO:0000269|PubMed:17897319, CC ECO:0000269|PubMed:25753619, ECO:0000269|PubMed:28082515}; Multi-pass CC membrane protein {ECO:0000269|PubMed:36113465}. Melanosome membrane CC {ECO:0000269|PubMed:22649030}; Multi-pass membrane protein CC {ECO:0000269|PubMed:36113465}. Note=AP-3 complex is required for CC localization to the lysosome. {ECO:0000269|PubMed:25753619}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Lysosome membrane CC {ECO:0000269|PubMed:18337546, ECO:0000269|PubMed:27148969}; Multi-pass CC membrane protein {ECO:0000269|PubMed:36113465}. Cell membrane CC {ECO:0000269|PubMed:18337546, ECO:0000269|PubMed:27148969}; Multi-pass CC membrane protein {ECO:0000269|PubMed:36113465}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=O60931-1; Sequence=Displayed; CC Name=2; Synonyms=cystinosin-LKG {ECO:0000303|PubMed:22544350}; CC IsoId=O60931-2; Sequence=VSP_038377; CC -!- TISSUE SPECIFICITY: Strongly expressed in pancreas, kidney (adult and CC fetal), skeletal muscle, melanocytes and keratinocytes CC (PubMed:22649030). Expressed at lower levels in placenta and heart. CC Weakly expressed in lung, liver and brain (adult and fetal) CC (PubMed:22649030). {ECO:0000269|PubMed:22649030}. CC -!- TISSUE SPECIFICITY: [Isoform 2]: Represents 5-20 % of CTNS transcripts, CC with the exception of the testis that expresses both isoforms in equal CC proportions. {ECO:0000269|PubMed:22649030}. CC -!- DOMAIN: The lysosomal targeting motif, together with the second PQ-loop CC mediate targeting to the lysosome. {ECO:0000269|PubMed:11150305}. CC -!- DISEASE: Cystinosis, nephropathic type (CTNS) [MIM:219800]: A form of CC cystinosis, a lysosomal storage disease due to defective transport of CC cystine across the lysosomal membrane. This results in cystine CC accumulation and crystallization in the cells causing widespread tissue CC damage. The classical nephropathic form has onset in the first year of CC life and is characterized by a polyuro-polydipsic syndrome, marked CC height-weight growth delay, generalized impaired proximal tubular CC reabsorptive capacity, with severe fluid-electrolyte balance CC alterations, renal failure, ocular symptoms and other systemic CC complications. {ECO:0000269|PubMed:10482956, CC ECO:0000269|PubMed:10556299, ECO:0000269|PubMed:11689434, CC ECO:0000269|PubMed:12204010, ECO:0000269|PubMed:12442267, CC ECO:0000269|PubMed:12825071, ECO:0000269|PubMed:15128704, CC ECO:0000269|PubMed:19852576, ECO:0000269|PubMed:21786142, CC ECO:0000269|PubMed:22232659, ECO:0000269|PubMed:22450360, CC ECO:0000269|PubMed:9792862}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Cystinosis, adult, non-nephropathic type (CTNSANN) CC [MIM:219750]: A form of cystinosis, a lysosomal storage disease due to CC defective transport of cystine across the lysosomal membrane. This CC results in cystine accumulation and crystallization in the cells CC causing widespread tissue damage. Cystinosis adult non-nephropathic CC type is characterized by ocular features and a benign course. Patients CC manifest mild photophobia due to conjunctival and corneal cystine CC crystals. {ECO:0000269|PubMed:10625078, ECO:0000269|PubMed:15128704}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Cystinosis, late-onset juvenile or adolescent nephropathic CC type (CTNSJAN) [MIM:219900]: A form of cystinosis, a lysosomal storage CC disease due to defective transport of cystine across the lysosomal CC membrane. This results in cystine accumulation and crystallization in CC the cells causing widespread tissue damage. Late-onset juvenile or CC adolescent nephropathic cystinosis is an intermediated form, CC manifesting first at age 10 to 12 years with proteinuria due to CC glomerular damage rather than with the manifestations of tubular damage CC that occur first in infantile cystinosis. There is no excess amino CC aciduria and stature is normal. Photophobia, late development of CC pigmentary retinopathy, and chronic headaches are features. CC {ECO:0000269|PubMed:10444339, ECO:0000269|PubMed:10556299, CC ECO:0000269|PubMed:12442267, ECO:0000269|PubMed:15128704, CC ECO:0000269|PubMed:28082515, ECO:0000269|PubMed:9792862}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the cystinosin family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; Y15924; CAA75882.1; -; Genomic_DNA. DR EMBL; Y15925; CAA75882.1; JOINED; Genomic_DNA. DR EMBL; Y15926; CAA75882.1; JOINED; Genomic_DNA. DR EMBL; Y15927; CAA75882.1; JOINED; Genomic_DNA. DR EMBL; Y15928; CAA75882.1; JOINED; Genomic_DNA. DR EMBL; Y15929; CAA75882.1; JOINED; Genomic_DNA. DR EMBL; Y15930; CAA75882.1; JOINED; Genomic_DNA. DR EMBL; Y15931; CAA75882.1; JOINED; Genomic_DNA. DR EMBL; Y15932; CAA75882.1; JOINED; Genomic_DNA. DR EMBL; Y15933; CAA75882.1; JOINED; Genomic_DNA. DR EMBL; AJ222967; CAA11021.1; -; mRNA. DR EMBL; AF168787; AAF43102.1; -; Genomic_DNA. DR EMBL; AK292019; BAF84708.1; -; mRNA. DR EMBL; AC027796; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC132942; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471108; EAW90495.1; -; Genomic_DNA. DR EMBL; CH471108; EAW90494.1; -; Genomic_DNA. DR EMBL; CH471108; EAW90496.1; -; Genomic_DNA. DR EMBL; BC032850; AAH32850.1; -; mRNA. DR EMBL; AH008011; AAD45630.1; -; Genomic_DNA. DR CCDS; CCDS11031.1; -. [O60931-1] DR CCDS; CCDS32530.1; -. [O60931-2] DR RefSeq; NP_001026851.2; NM_001031681.2. [O60931-2] DR RefSeq; NP_004928.2; NM_004937.2. [O60931-1] DR PDB; 8DKE; EM; 3.18 A; P=1-362. DR PDB; 8DKI; EM; 3.32 A; P=1-362. DR PDB; 8DKM; EM; 3.39 A; P=1-362. DR PDB; 8DKW; EM; 3.09 A; P=1-362. DR PDB; 8DKX; EM; 3.00 A; P=1-362. DR PDB; 8DYP; X-ray; 3.40 A; A=25-356. DR PDBsum; 8DKE; -. DR PDBsum; 8DKI; -. DR PDBsum; 8DKM; -. DR PDBsum; 8DKW; -. DR PDBsum; 8DKX; -. DR PDBsum; 8DYP; -. DR AlphaFoldDB; O60931; -. DR EMDB; EMD-27488; -. DR EMDB; EMD-27489; -. DR EMDB; EMD-27490; -. DR EMDB; EMD-27492; -. DR EMDB; EMD-27493; -. DR SMR; O60931; -. DR BioGRID; 107878; 4. DR IntAct; O60931; 1. DR STRING; 9606.ENSP00000371294; -. DR ChEMBL; CHEMBL4630803; -. DR DrugBank; DB00138; Cystine. DR TCDB; 2.A.43.1.1; the lysosomal cystine transporter (lct) family. DR GlyCosmos; O60931; 7 sites, No reported glycans. DR GlyGen; O60931; 7 sites. DR iPTMnet; O60931; -. DR PhosphoSitePlus; O60931; -. DR BioMuta; CTNS; -. DR jPOST; O60931; -. DR MassIVE; O60931; -. DR MaxQB; O60931; -. DR PaxDb; 9606-ENSP00000371294; -. DR PeptideAtlas; O60931; -. DR ProteomicsDB; 49677; -. [O60931-2] DR Antibodypedia; 23081; 210 antibodies from 27 providers. DR DNASU; 1497; -. DR Ensembl; ENST00000046640.9; ENSP00000046640.4; ENSG00000040531.16. [O60931-1] DR Ensembl; ENST00000381870.8; ENSP00000371294.3; ENSG00000040531.16. [O60931-2] DR Ensembl; ENST00000673965.1; ENSP00000500995.1; ENSG00000040531.16. [O60931-1] DR GeneID; 1497; -. DR KEGG; hsa:1497; -. DR MANE-Select; ENST00000046640.9; ENSP00000046640.4; NM_004937.3; NP_004928.2. DR UCSC; uc002fwa.4; human. [O60931-1] DR AGR; HGNC:2518; -. DR CTD; 1497; -. DR DisGeNET; 1497; -. DR GeneCards; CTNS; -. DR GeneReviews; CTNS; -. DR HGNC; HGNC:2518; CTNS. DR HPA; ENSG00000040531; Low tissue specificity. DR MalaCards; CTNS; -. DR MIM; 219750; phenotype. DR MIM; 219800; phenotype. DR MIM; 219900; phenotype. DR MIM; 606272; gene. DR neXtProt; NX_O60931; -. DR OpenTargets; ENSG00000040531; -. DR Orphanet; 411629; Infantile nephropathic cystinosis. DR Orphanet; 411634; Juvenile nephropathic cystinosis. DR Orphanet; 411641; Ocular cystinosis. DR PharmGKB; PA27019; -. DR VEuPathDB; HostDB:ENSG00000040531; -. DR eggNOG; KOG3145; Eukaryota. DR GeneTree; ENSGT00390000005338; -. DR HOGENOM; CLU_046327_1_0_1; -. DR InParanoid; O60931; -. DR OMA; WIDVIYT; -. DR OrthoDB; 179669at2759; -. DR PhylomeDB; O60931; -. DR TreeFam; TF313589; -. DR PathwayCommons; O60931; -. DR Reactome; R-HSA-425393; Transport of inorganic cations/anions and amino acids/oligopeptides. DR Reactome; R-HSA-5223345; Miscellaneous transport and binding events. DR SignaLink; O60931; -. DR BioGRID-ORCS; 1497; 18 hits in 1157 CRISPR screens. DR ChiTaRS; CTNS; human. DR GeneWiki; CTNS_(gene); -. DR GenomeRNAi; 1497; -. DR Pharos; O60931; Tbio. DR PRO; PR:O60931; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; O60931; Protein. DR Bgee; ENSG00000040531; Expressed in right adrenal gland cortex and 169 other cell types or tissues. DR ExpressionAtlas; O60931; baseline and differential. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA. DR GO; GO:0005770; C:late endosome; IDA:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB. DR GO; GO:0005764; C:lysosome; IDA:MGI. DR GO; GO:0042470; C:melanosome; IDA:UniProtKB. DR GO; GO:0033162; C:melanosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0015184; F:L-cystine transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0015295; F:solute:proton symporter activity; IDA:UniProtKB. DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl. DR GO; GO:0006520; P:amino acid metabolic process; NAS:UniProtKB. DR GO; GO:0046034; P:ATP metabolic process; IMP:UniProtKB. DR GO; GO:0007420; P:brain development; IMP:UniProtKB. DR GO; GO:1904970; P:brush border assembly; IEA:Ensembl. DR GO; GO:0050890; P:cognition; IMP:UniProtKB. DR GO; GO:0006749; P:glutathione metabolic process; IMP:UniProtKB. DR GO; GO:0007625; P:grooming behavior; IEA:Ensembl. DR GO; GO:0015811; P:L-cystine transport; IDA:UniProtKB. DR GO; GO:0002088; P:lens development in camera-type eye; IEA:Ensembl. DR GO; GO:0007616; P:long-term memory; IEA:Ensembl. DR GO; GO:0042438; P:melanin biosynthetic process; IEA:UniProtKB-KW. DR GO; GO:0006811; P:monoatomic ion transport; TAS:Reactome. DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0010730; P:negative regulation of hydrogen peroxide biosynthetic process; IEA:Ensembl. DR GO; GO:0010918; P:positive regulation of mitochondrial membrane potential; IEA:Ensembl. DR GO; GO:2000611; P:positive regulation of thyroid hormone generation; IEA:Ensembl. DR GO; GO:1904263; P:positive regulation of TORC1 signaling; IEA:Ensembl. DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW. DR GO; GO:0072158; P:proximal tubule morphogenesis; IEA:Ensembl. DR GO; GO:0048021; P:regulation of melanin biosynthetic process; IMP:UniProtKB. DR GO; GO:1903432; P:regulation of TORC1 signaling; IDA:UniProtKB. DR GO; GO:0097018; P:renal albumin absorption; IEA:Ensembl. DR GO; GO:0035623; P:renal glucose absorption; IEA:Ensembl. DR GO; GO:0097291; P:renal phosphate ion absorption; IEA:Ensembl. DR GO; GO:0070295; P:renal water absorption; IEA:Ensembl. DR GO; GO:0030878; P:thyroid gland development; IEA:Ensembl. DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome. DR GO; GO:0008542; P:visual learning; IEA:Ensembl. DR Gene3D; 1.20.1280.290; -; 1. DR InterPro; IPR005282; LC_transporter. DR InterPro; IPR006603; PQ-loop_rpt. DR NCBIfam; TIGR00951; 2A43; 1. DR PANTHER; PTHR13131; CYSTINOSIN; 1. DR PANTHER; PTHR13131:SF5; CYSTINOSIN; 1. DR Pfam; PF04193; PQ-loop; 2. DR SMART; SM00679; CTNS; 2. DR Genevisible; O60931; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; KW Direct protein sequencing; Disease variant; Glycoprotein; Lysosome; KW Melanin biosynthesis; Membrane; Protein transport; Reference proteome; KW Repeat; Signal; Symport; Transmembrane; Transmembrane helix; Transport. FT SIGNAL 1..22 FT /evidence="ECO:0000269|PubMed:28082515" FT CHAIN 23..367 FT /note="Cystinosin" FT /id="PRO_0000205514" FT TOPO_DOM 23..125 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:36113465" FT TRANSMEM 126..150 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:36113465, FT ECO:0007744|PDB:8DKE, ECO:0007744|PDB:8DKI, FT ECO:0007744|PDB:8DKM, ECO:0007744|PDB:8DKW, FT ECO:0007744|PDB:8DKX, ECO:0007744|PDB:8DYP" FT TOPO_DOM 151..159 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:36113465" FT TRANSMEM 160..179 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:36113465, FT ECO:0007744|PDB:8DKE, ECO:0007744|PDB:8DKI, FT ECO:0007744|PDB:8DKM, ECO:0007744|PDB:8DKW, FT ECO:0007744|PDB:8DKX, ECO:0007744|PDB:8DYP" FT TOPO_DOM 180..202 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:36113465" FT TRANSMEM 203..225 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:36113465, FT ECO:0007744|PDB:8DKE, ECO:0007744|PDB:8DKI, FT ECO:0007744|PDB:8DKM, ECO:0007744|PDB:8DKW, FT ECO:0007744|PDB:8DKX, ECO:0007744|PDB:8DYP" FT TOPO_DOM 226..234 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:36113465" FT TRANSMEM 235..257 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:36113465, FT ECO:0007744|PDB:8DKE, ECO:0007744|PDB:8DKI, FT ECO:0007744|PDB:8DKM, ECO:0007744|PDB:8DKW, FT ECO:0007744|PDB:8DKX, ECO:0007744|PDB:8DYP" FT TOPO_DOM 258..263 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:36113465" FT TRANSMEM 264..289 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:36113465, FT ECO:0007744|PDB:8DKE, ECO:0007744|PDB:8DKI, FT ECO:0007744|PDB:8DKM, ECO:0007744|PDB:8DKW, FT ECO:0007744|PDB:8DKX, ECO:0007744|PDB:8DYP" FT TOPO_DOM 290..298 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:36113465" FT TRANSMEM 299..308 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:36113465, FT ECO:0007744|PDB:8DKE, ECO:0007744|PDB:8DKI, FT ECO:0007744|PDB:8DKM, ECO:0007744|PDB:8DKW, FT ECO:0007744|PDB:8DKX, ECO:0007744|PDB:8DYP" FT TOPO_DOM 309..331 FT /note="Lumenal" FT /evidence="ECO:0000269|PubMed:36113465" FT TRANSMEM 332..354 FT /note="Helical" FT /evidence="ECO:0000269|PubMed:36113465, FT ECO:0007744|PDB:8DKE, ECO:0007744|PDB:8DKI, FT ECO:0007744|PDB:8DKM, ECO:0007744|PDB:8DKW, FT ECO:0007744|PDB:8DKX, ECO:0007744|PDB:8DYP" FT TOPO_DOM 355..367 FT /note="Cytoplasmic" FT /evidence="ECO:0000269|PubMed:36113465" FT DOMAIN 123..189 FT /note="PQ-loop 1" FT /evidence="ECO:0000255" FT DOMAIN 263..328 FT /note="PQ-loop 2" FT /evidence="ECO:0000255" FT MOTIF 362..366 FT /note="Lysosomal targeting motif" FT /evidence="ECO:0000255, ECO:0000269|PubMed:11150305" FT BINDING 166 FT /ligand="L-cystine" FT /ligand_id="ChEBI:CHEBI:35491" FT /evidence="ECO:0000269|PubMed:36113465, FT ECO:0007744|PDB:8DKM" FT BINDING 205 FT /ligand="H(+)" FT /ligand_id="ChEBI:CHEBI:15378" FT /evidence="ECO:0000305|PubMed:36113465" FT BINDING 273 FT /ligand="L-cystine" FT /ligand_id="ChEBI:CHEBI:35491" FT /evidence="ECO:0000269|PubMed:36113465" FT BINDING 280 FT /ligand="L-cystine" FT /ligand_id="ChEBI:CHEBI:35491" FT /evidence="ECO:0000269|PubMed:36113465" FT BINDING 281 FT /ligand="L-cystine" FT /ligand_id="ChEBI:CHEBI:35491" FT /evidence="ECO:0000269|PubMed:36113465" FT BINDING 301 FT /ligand="L-cystine" FT /ligand_id="ChEBI:CHEBI:35491" FT /evidence="ECO:0000269|PubMed:36113465, FT ECO:0007744|PDB:8DKM" FT BINDING 305 FT /ligand="H(+)" FT /ligand_id="ChEBI:CHEBI:15378" FT /note="protonated residue following cystine-binding" FT /evidence="ECO:0000269|PubMed:22232659, FT ECO:0000305|PubMed:36113465" FT BINDING 305 FT /ligand="L-cystine" FT /ligand_id="ChEBI:CHEBI:35491" FT /evidence="ECO:0000269|PubMed:36113465" FT BINDING 346 FT /ligand="H(+)" FT /ligand_id="ChEBI:CHEBI:15378" FT /evidence="ECO:0000305|PubMed:36113465" FT CARBOHYD 36 FT /note="N-linked (GlcNAc...) (high mannose) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:28082515" FT CARBOHYD 41 FT /note="N-linked (GlcNAc...) (high mannose) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:28082515" FT CARBOHYD 51 FT /note="N-linked (GlcNAc...) (high mannose) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:28082515" FT CARBOHYD 66 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:28082515" FT CARBOHYD 84 FT /note="N-linked (GlcNAc...) (high mannose) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:28082515" FT CARBOHYD 104 FT /note="N-linked (GlcNAc...) (high mannose) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:28082515" FT CARBOHYD 107 FT /note="N-linked (GlcNAc...) (high mannose) asparagine" FT /evidence="ECO:0000255, ECO:0000269|PubMed:28082515" FT VAR_SEQ 363..367 FT /note="YDQLN -> LQAARTGSGSRLRQDWAPSLQPKALPQTTSVSASSLKG (in FT isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_038377" FT VARIANT 42 FT /note="V -> I (does not affect cystine transport; FT dbSNP:rs35086888)" FT /evidence="ECO:0000269|PubMed:10556299, FT ECO:0000269|PubMed:15128704" FT /id="VAR_010285" FT VARIANT 67..73 FT /note="Missing (in CTNSJAN; protein misfolding leading to FT decreased stability; decreased cystine transport)" FT /evidence="ECO:0000269|PubMed:15128704, FT ECO:0000269|PubMed:28082515, ECO:0000269|PubMed:9792862" FT /id="VAR_010674" FT VARIANT 110 FT /note="G -> V (in CTNS; atypical; does not affect cystine FT transport; dbSNP:rs121908129)" FT /evidence="ECO:0000269|PubMed:12442267, FT ECO:0000269|PubMed:15128704" FT /id="VAR_037318" FT VARIANT 133 FT /note="I -> F (in CTNS; does not affect cystine transport; FT dbSNP:rs886040970)" FT /evidence="ECO:0000269|PubMed:10482956, FT ECO:0000269|PubMed:15128704" FT /id="VAR_010677" FT VARIANT 139 FT /note="S -> F (in CTNS; atypical; abolished cystine FT transport; dbSNP:rs267606754)" FT /evidence="ECO:0000269|PubMed:10556299, FT ECO:0000269|PubMed:15128704" FT /id="VAR_010678" FT VARIANT 141 FT /note="S -> F (in CTNS; abolished cystine transport)" FT /evidence="ECO:0000269|PubMed:15128704" FT /id="VAR_084186" FT VARIANT 151 FT /note="R -> G (in CTNS; dbSNP:rs1555563010)" FT /evidence="ECO:0000269|PubMed:21786142" FT /id="VAR_067490" FT VARIANT 154 FT /note="S -> SPCS (in CTNSJAN; decreased cystine transport)" FT /evidence="ECO:0000269|PubMed:10556299, FT ECO:0000269|PubMed:15128704" FT /id="VAR_010679" FT VARIANT 157 FT /note="G -> D (in CTNS)" FT /evidence="ECO:0000269|PubMed:21786142" FT /id="VAR_067491" FT VARIANT 158 FT /note="L -> P (in CTNS; abolished cystine transport; FT dbSNP:rs113994206)" FT /evidence="ECO:0000269|PubMed:10482956, FT ECO:0000269|PubMed:15128704" FT /id="VAR_010680" FT VARIANT 169 FT /note="G -> D (in CTNS; abolished cystine transport; FT dbSNP:rs121908126)" FT /evidence="ECO:0000269|PubMed:15128704, FT ECO:0000269|PubMed:9792862" FT /id="VAR_010286" FT VARIANT 173 FT /note="Y -> C (in CTNS; dbSNP:rs1555563446)" FT /evidence="ECO:0000269|PubMed:21786142" FT /id="VAR_067492" FT VARIANT 177 FT /note="N -> S (in CTNS; abolished cystine transport)" FT /evidence="ECO:0000269|PubMed:15128704, FT ECO:0000269|PubMed:19852576" FT /id="VAR_067493" FT VARIANT 177 FT /note="N -> T (in CTNSJAN)" FT /evidence="ECO:0000269|PubMed:12442267" FT /id="VAR_037319" FT VARIANT 182 FT /note="W -> R (in CTNS; does not affect cystine transport; FT dbSNP:rs764168489)" FT /evidence="ECO:0000269|PubMed:15128704, FT ECO:0000269|PubMed:9792862" FT /id="VAR_010681" FT VARIANT 197 FT /note="G -> R (in CTNSANN; decreased cystine transport; FT dbSNP:rs113994207)" FT /evidence="ECO:0000269|PubMed:10625078, FT ECO:0000269|PubMed:15128704" FT /id="VAR_010682" FT VARIANT 200 FT /note="P -> L (in CTNSJAN; decreased cystine transport)" FT /evidence="ECO:0000269|PubMed:12442267, FT ECO:0000269|PubMed:15128704" FT /id="VAR_037320" FT VARIANT 205 FT /note="D -> N (in CTNS; abolished cystine transport; FT dbSNP:rs113994208)" FT /evidence="ECO:0000269|PubMed:15128704, FT ECO:0000269|PubMed:9792862" FT /id="VAR_010683" FT VARIANT 205 FT /note="Missing (in CTNS; abolished cystine transport)" FT /evidence="ECO:0000269|PubMed:10556299, FT ECO:0000269|PubMed:15128704, ECO:0000269|PubMed:9792862" FT /id="VAR_010684" FT VARIANT 222 FT /note="Q -> R (in CTNS; partial relocation to the cell FT membrane; abolished cystine transport; dbSNP:rs1327959008)" FT /evidence="ECO:0000269|PubMed:12442267, FT ECO:0000269|PubMed:15128704" FT /id="VAR_037321" FT VARIANT 260 FT /note="T -> I (slightly decreased cystine transport; FT dbSNP:rs161400)" FT /evidence="ECO:0000269|PubMed:10068513, FT ECO:0000269|PubMed:10673275, ECO:0000269|PubMed:12825071, FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15128704, FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:9537412, FT ECO:0000269|Ref.5" FT /id="VAR_060371" FT VARIANT 270 FT /note="Missing (in CTNS; abolished cystine transport)" FT /evidence="ECO:0000269|PubMed:10556299, FT ECO:0000269|PubMed:15128704" FT /id="VAR_010689" FT VARIANT 280 FT /note="K -> R (in CTNSJAN; abolished cystine transport)" FT /evidence="ECO:0000269|PubMed:10444339, FT ECO:0000269|PubMed:15128704" FT /id="VAR_010287" FT VARIANT 287 FT /note="M -> I (in CTNS; dbSNP:rs922106812)" FT /evidence="ECO:0000269|PubMed:12825071" FT /id="VAR_067494" FT VARIANT 288 FT /note="N -> K (in CTNS; abolished cystine transport)" FT /evidence="ECO:0000269|PubMed:12442267, FT ECO:0000269|PubMed:15128704" FT /id="VAR_037322" FT VARIANT 292 FT /note="K -> R (found in patients with cystinosis; uncertain FT significance; dbSNP:rs1800527)" FT /evidence="ECO:0000269|PubMed:9792862" FT /id="VAR_012314" FT VARIANT 298 FT /note="S -> N (in CTNS; does not affect cystine transport; FT dbSNP:rs1212133760)" FT /evidence="ECO:0000269|PubMed:15128704, FT ECO:0000269|PubMed:9792862" FT /id="VAR_012315" FT VARIANT 305 FT /note="D -> G (in CTNS; dbSNP:rs1263951539)" FT /evidence="ECO:0000269|PubMed:9792862" FT /id="VAR_010690" FT VARIANT 305 FT /note="D -> Y (in CTNS; abolished cystine transport)" FT /evidence="ECO:0000269|PubMed:10556299, FT ECO:0000269|PubMed:15128704" FT /id="VAR_010691" FT VARIANT 308 FT /note="G -> R (in CTNS; abolished cystine transport; FT dbSNP:rs746307931)" FT /evidence="ECO:0000269|PubMed:10556299, FT ECO:0000269|PubMed:11689434, ECO:0000269|PubMed:12825071, FT ECO:0000269|PubMed:15128704, ECO:0000269|PubMed:22232659, FT ECO:0000269|PubMed:9792862" FT /id="VAR_010692" FT VARIANT 308 FT /note="G -> V (in CTNS; dbSNP:rs908965524)" FT /evidence="ECO:0000269|PubMed:12204010" FT /id="VAR_067495" FT VARIANT 309 FT /note="G -> D (in CTNS)" FT /evidence="ECO:0000269|PubMed:22450360" FT /id="VAR_067496" FT VARIANT 323 FT /note="N -> K (in CTNSJAN; abolished cystine transport; FT dbSNP:rs121908128)" FT /evidence="ECO:0000269|PubMed:10444339, FT ECO:0000269|PubMed:15128704, ECO:0000269|PubMed:22450360" FT /id="VAR_010288" FT VARIANT 337 FT /note="G -> R (in CTNS)" FT /evidence="ECO:0000269|PubMed:12825071" FT /id="VAR_067497" FT VARIANT 338 FT /note="L -> P (in CTNS; abolished cystine transport)" FT /evidence="ECO:0000269|PubMed:10556299, FT ECO:0000269|PubMed:15128704" FT /id="VAR_010694" FT VARIANT 338 FT /note="L -> R (in CTNS)" FT /evidence="ECO:0000269|PubMed:19852576" FT /id="VAR_067498" FT VARIANT 339 FT /note="G -> R (in CTNS; abolished cystine transport; FT dbSNP:rs121908127)" FT /evidence="ECO:0000269|PubMed:10556299, FT ECO:0000269|PubMed:12204010, ECO:0000269|PubMed:12825071, FT ECO:0000269|PubMed:15128704, ECO:0000269|PubMed:9792862" FT /id="VAR_010695" FT VARIANT 343..346 FT /note="Missing (in CTNS; partial relocation to the cell FT membrane; abolished cystine transport)" FT /evidence="ECO:0000269|PubMed:10556299, FT ECO:0000269|PubMed:15128704" FT /id="VAR_010697" FT VARIANT 346..349 FT /note="Missing (in CTNS; partial relocation to the cell FT membrane; abolished cystine transport)" FT /evidence="ECO:0000269|PubMed:12442267, FT ECO:0000269|PubMed:15128704" FT /id="VAR_037323" FT VARIANT 346 FT /note="D -> N (in CTNS; atypical; slightly decreased FT cystine transport; dbSNP:rs757535731)" FT /evidence="ECO:0000269|PubMed:10556299, FT ECO:0000269|PubMed:15128704" FT /id="VAR_010698" FT VARIANT 349 FT /note="F -> FDVEF (in CTNS; abolished cystine transport)" FT /evidence="ECO:0000269|PubMed:12442267, FT ECO:0000269|PubMed:15128704" FT /id="VAR_037324" FT MUTAGEN 66 FT /note="N->A: Decreased glycosylation." FT /evidence="ECO:0000269|PubMed:28082515" FT MUTAGEN 131 FT /note="G->S,D: Gain-of-function mutant that shows higher FT transport of cystine." FT /evidence="ECO:0000269|PubMed:29467429" FT MUTAGEN 134 FT /note="Y->A,F: Nearly abolished cystine transport." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 137 FT /note="A->V: Gain-of-function mutant that shows higher FT transport of cystine." FT /evidence="ECO:0000269|PubMed:29467429" FT MUTAGEN 138 FT /note="W->F: Abolished cystine transport." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 142 FT /note="F->A: Abolished cystine transport." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 143 FT /note="Y->F: Slightly decreased midpoint potential. FT Impaired dielectric distance." FT /evidence="ECO:0000269|PubMed:22232659" FT MUTAGEN 145 FT /note="Q->A: Increased cystine uptake activity." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 152 FT /note="R->Q: Impaired dielectric distance." FT /evidence="ECO:0000269|PubMed:22232659" FT MUTAGEN 161 FT /note="D->N: Strongly reduced steady-state transport FT current. Slightly decreased midpoint potential." FT /evidence="ECO:0000269|PubMed:22232659" FT MUTAGEN 166 FT /note="N->A: Abolished cystine transport." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 170 FT /note="F->A: Strongly decreased cystine transport." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 205 FT /note="D->A,N: Nearly abolished cystine transport. Impaired FT pH-dependent conformational shift." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 205 FT /note="D->N: Abolished steady-state transport current. FT Decreased midpoint potential." FT /evidence="ECO:0000269|PubMed:22232659" FT MUTAGEN 211 FT /note="H->F: Accelerated the time course." FT /evidence="ECO:0000269|PubMed:22232659" FT MUTAGEN 270 FT /note="S->T: Gain-of-function mutant that shows higher FT transport of cystine." FT /evidence="ECO:0000269|PubMed:29467429" FT MUTAGEN 273 FT /note="K->Q: Abolished cystine transport." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 274 FT /note="L->F: Gain-of-function mutant that shows higher FT transport of cystine." FT /evidence="ECO:0000269|PubMed:29467429" FT MUTAGEN 280..288 FT /note="Missing: In delta(A) mutant; abolished localization FT to the lysosome; when associated with deletion of FT 362-G--L-366." FT /evidence="ECO:0000269|PubMed:11150305" FT MUTAGEN 280 FT /note="K->R: Abolished cystine transport." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 281..284 FT /note="YFPQ->AAAA: In mu(a) mutant; abolished localization FT to the lysosome; when associated with deletion of FT 362-G--L-366." FT /evidence="ECO:0000269|PubMed:11150305" FT MUTAGEN 281 FT /note="Y->F: Strongly decreased cystine transport. FT Decreased midpoint potential. Accelerated the time course." FT /evidence="ECO:0000269|PubMed:22232659, FT ECO:0000269|PubMed:36113465" FT MUTAGEN 284 FT /note="Q->A: Increased cystine uptake activity." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 286..289 FT /note="YMNF->AAAA: In mu(b) mutant; does not abolish FT localization to the lysosome; when associated with deletion FT of 362-G--L-366." FT /evidence="ECO:0000269|PubMed:11150305" FT MUTAGEN 289..298 FT /note="Missing: In delta(B) mutant; does not abolish FT localization to the lysosome; when associated with deletion FT of 362-G--L-366." FT /evidence="ECO:0000269|PubMed:11150305" FT MUTAGEN 301 FT /note="N->A: Strongly decreased cystine transport." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 305 FT /note="D->E: Abolished steady-state transport current." FT /evidence="ECO:0000269|PubMed:22232659" FT MUTAGEN 305 FT /note="D->N: Abolished cystine transport. Abolished FT transient cxurrents. Abolished steady-state transport FT current." FT /evidence="ECO:0000269|PubMed:22232659, FT ECO:0000269|PubMed:36113465" FT MUTAGEN 309 FT /note="G->C,S: Gain-of-function mutant that shows higher FT transport of cystine." FT /evidence="ECO:0000269|PubMed:29467429" FT MUTAGEN 312 FT /note="S->N: Gain-of-function mutant that shows higher FT transport of cystine." FT /evidence="ECO:0000269|PubMed:29467429" FT MUTAGEN 319 FT /note="Q->A: Strongly decreased cystine transport." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 335 FT /note="K->A: Nearly abolished cystine transport." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 335 FT /note="K->Q: Abolished steady-state transport current. FT Decreased midpoint potential. Impaired dielectric distance. FT Accelerated the time course." FT /evidence="ECO:0000269|PubMed:22232659" FT MUTAGEN 346 FT /note="D->N: Abolished pH-dependent conformational shift." FT /evidence="ECO:0000269|PubMed:36113465" FT MUTAGEN 362..366 FT /note="Missing: Strongly reduced but not abolished FT localization to the lysosome, leading to partial relocation FT to the cell membrane. Abolished localization to the FT lysosome; when associated with 281-A--A-284 or deletion of FT 280-K--N-288. Does not abolish localization to the FT lysosome; when associated with 286-A--A-289 or deletion of FT 289-F--S-298." FT /evidence="ECO:0000269|PubMed:11150305, FT ECO:0000269|PubMed:29467429" FT MUTAGEN 362 FT /note="G->A: Does not affect localization to the lysosome." FT /evidence="ECO:0000269|PubMed:11150305" FT MUTAGEN 363 FT /note="Y->A: Strongly reduced but not abolished FT localization to the lysosome, leading to partial relocation FT to the cell membrane." FT /evidence="ECO:0000269|PubMed:11150305, FT ECO:0000269|PubMed:29467429" FT MUTAGEN 364 FT /note="D->A: Does not affect localization to the lysosome." FT /evidence="ECO:0000269|PubMed:11150305" FT MUTAGEN 365 FT /note="Q->A: Does not affect localization to the lysosome." FT /evidence="ECO:0000269|PubMed:11150305" FT MUTAGEN 366 FT /note="L->A: Strongly reduced but not abolished FT localization to the lysosome, leading to partial relocation FT to the cell membrane." FT /evidence="ECO:0000269|PubMed:11150305, FT ECO:0000269|PubMed:29467429" FT STRAND 30..35 FT /evidence="ECO:0007829|PDB:8DKX" FT STRAND 39..43 FT /evidence="ECO:0007829|PDB:8DKX" FT STRAND 45..48 FT /evidence="ECO:0007829|PDB:8DKX" FT STRAND 54..56 FT /evidence="ECO:0007829|PDB:8DKX" FT STRAND 58..62 FT /evidence="ECO:0007829|PDB:8DKX" FT STRAND 64..67 FT /evidence="ECO:0007829|PDB:8DKX" FT STRAND 69..71 FT /evidence="ECO:0007829|PDB:8DKX" FT STRAND 76..78 FT /evidence="ECO:0007829|PDB:8DKX" FT STRAND 86..91 FT /evidence="ECO:0007829|PDB:8DKX" FT STRAND 93..101 FT /evidence="ECO:0007829|PDB:8DKX" FT STRAND 106..108 FT /evidence="ECO:0007829|PDB:8DKX" FT STRAND 112..119 FT /evidence="ECO:0007829|PDB:8DKX" FT HELIX 121..138 FT /evidence="ECO:0007829|PDB:8DKX" FT TURN 139..141 FT /evidence="ECO:0007829|PDB:8DKW" FT HELIX 142..152 FT /evidence="ECO:0007829|PDB:8DKX" FT STRAND 156..158 FT /evidence="ECO:0007829|PDB:8DKX" FT HELIX 160..181 FT /evidence="ECO:0007829|PDB:8DKX" FT HELIX 184..193 FT /evidence="ECO:0007829|PDB:8DKX" FT HELIX 203..225 FT /evidence="ECO:0007829|PDB:8DKX" FT HELIX 235..257 FT /evidence="ECO:0007829|PDB:8DKX" FT STRAND 258..260 FT /evidence="ECO:0007829|PDB:8DKX" FT TURN 261..263 FT /evidence="ECO:0007829|PDB:8DKW" FT HELIX 264..290 FT /evidence="ECO:0007829|PDB:8DKX" FT HELIX 299..322 FT /evidence="ECO:0007829|PDB:8DKX" FT TURN 328..331 FT /evidence="ECO:0007829|PDB:8DKE" FT TURN 333..338 FT /evidence="ECO:0007829|PDB:8DKX" FT HELIX 339..355 FT /evidence="ECO:0007829|PDB:8DKX" FT MUTAGEN O60931-2:396..400 FT /note="Missing: Abolished localization to the cell FT membrane. Does not affect cystine transport." FT /evidence="ECO:0000269|PubMed:27148969" SQ SEQUENCE 367 AA; 41738 MW; 9343889CD7576908 CRC64; MIRNWLTIFI LFPLKLVEKC ESSVSLTVPP VVKLENGSST NVSLTLRPPL NATLVITFEI TFRSKNITIL ELPDEVVVPP GVTNSSFQVT SQNVGQLTVY LHGNHSNQTG PRIRFLVIRS SAISIINQVI GWIYFVAWSI SFYPQVIMNW RRKSVIGLSF DFVALNLTGF VAYSVFNIGL LWVPYIKEQF LLKYPNGVNP VNSNDVFFSL HAVVLTLIII VQCCLYERGG QRVSWPAIGF LVLAWLFAFV TMIVAAVGVT TWLQFLFCFS YIKLAVTLVK YFPQAYMNFY YKSTEGWSIG NVLLDFTGGS FSLLQMFLQS YNNDQWTLIF GDPTKFGLGV FSIVFDVVFF IQHFCLYRKR PGYDQLN //