CTNS_MOUSE
ID CTNS_MOUSE Reviewed; 367 AA.
AC P57757;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 21-FEB-2001, sequence version 1.
DT 03-AUG-2022, entry version 141.
DE RecName: Full=Cystinosin {ECO:0000303|PubMed:11121245};
DE Flags: Precursor;
GN Name=Ctns {ECO:0000303|PubMed:11121245, ECO:0000312|MGI:MGI:1932872};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11121245; DOI=10.1186/1471-2164-1-2;
RA Cherqui S., Kalatzis V., Forestier L., Poras I., Antignac C.;
RT "Identification and characterisation of the murine homologue of the gene
RT responsible for cystinosis, Ctns.";
RL BMC Genomics 1:2-2(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Mammary gland;
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 [4]
RP FUNCTION, SUBCELLULAR LOCATION, AND DISRUPTION PHENOTYPE.
RX PubMed=12370309; DOI=10.1128/mcb.22.21.7622-7632.2002;
RA Cherqui S., Sevin C., Hamard G., Kalatzis V., Sich M., Pequignot M.O.,
RA Gogat K., Abitbol M., Broyer M., Gubler M.C., Antignac C.;
RT "Intralysosomal cystine accumulation in mice lacking cystinosin, the
RT protein defective in cystinosis.";
RL Mol. Cell. Biol. 22:7622-7632(2002).
RN [5]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-66.
RX PubMed=19349973; DOI=10.1038/nbt.1532;
RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA Schiess R., Aebersold R., Watts J.D.;
RT "Mass-spectrometric identification and relative quantification of N-linked
RT cell surface glycoproteins.";
RL Nat. Biotechnol. 27:378-386(2009).
RN [6]
RP DISRUPTION PHENOTYPE.
RX PubMed=17977621; DOI=10.1016/j.neurobiolaging.2007.09.006;
RA Maurice T., Hippert C., Serratrice N., Dubois G., Jacquet C., Antignac C.,
RA Kremer E.J., Kalatzis V.;
RT "Cystine accumulation in the CNS results in severe age-related memory
RT deficits.";
RL Neurobiol. Aging 30:987-1000(2009).
RN [7]
RP DISRUPTION PHENOTYPE.
RX PubMed=21897743;
RA Simpson J., Nien C.J., Flynn K., Jester B., Cherqui S., Jester J.;
RT "Quantitative in vivo and ex vivo confocal microscopy analysis of corneal
RT cystine crystals in the Ctns knockout mouse.";
RL Mol. Vis. 17:2212-2220(2011).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
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 [9]
RP FUNCTION, DISRUPTION PHENOTYPE, INTERACTION WITH V-ATPASE AND RAGULATOR
RP COMPLEXES, INTERACTION WITH RRAGA AND RRAGC, AND MUTAGENESIS OF LYS-280.
RX PubMed=26449607; DOI=10.1681/asn.2014090937;
RA Andrzejewska Z., Nevo N., Thomas L., Chhuon C., Bailleux A., Chauvet V.,
RA Courtoy P.J., Chol M., Guerrera I.C., Antignac C.;
RT "Cystinosin is a component of the vacuolar H+-ATPase-Ragulator-Rag complex
RT controlling mammalian target of rapamycin complex 1 signaling.";
RL J. Am. Soc. Nephrol. 27:1678-1688(2016).
RN [10]
RP FUNCTION, AND MUTAGENESIS OF LYS-280.
RX PubMed=28465352; DOI=10.1074/jbc.m116.764076;
RA Zhang J., Johnson J.L., He J., Napolitano G., Ramadass M., Rocca C.,
RA Kiosses W.B., Bucci C., Xin Q., Gavathiotis E., Cuervo A.M., Cherqui S.,
RA Catz S.D.;
RT "Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate
RT intracellular trafficking of the chaperone-mediated autophagy receptor
RT LAMP2A.";
RL J. Biol. Chem. 292:10328-10346(2017).
CC -!- FUNCTION: Cystine/H(+) symporter that mediates export of cystine, the
CC oxidized dimer of cysteine, from lysosomes (PubMed:12370309). Plays an
CC important role in melanin synthesis by catalyzing cystine export from
CC melanosomes, possibly by inhibiting pheomelanin synthesis
CC (PubMed:22649030). In addition to cystine export, also acts as a
CC positive regulator of mTORC1 signaling in kidney proximal tubular
CC cells, via interactions with components of the v-ATPase and Ragulator
CC complexes (PubMed:26449607). Also involved in small GTPase-regulated
CC vesicle trafficking and lysosomal localization of LAMP2A, independently
CC of cystine transporter activity (PubMed:28465352).
CC {ECO:0000269|PubMed:12370309, ECO:0000269|PubMed:22649030,
CC ECO:0000269|PubMed:26449607, ECO:0000269|PubMed:28465352}.
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:0000250|UniProtKB:O60931};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:66173;
CC Evidence={ECO:0000250|UniProtKB:O60931};
CC -!- SUBUNIT: Interacts with components of the V-ATPase complex
CC (PubMed:26449607). Interacts with components of the Ragulator complex
CC (PubMed:26449607). Interacts with RRAGA/RagA and RRAGC/RagC
CC (PubMed:26449607). Interacts with AP-3 complex subunit mu (AP3M1 or
CC AP3M2) (By similarity). {ECO:0000250|UniProtKB:O60931,
CC ECO:0000269|PubMed:26449607}.
CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:12370309};
CC Multi-pass membrane protein {ECO:0000255}. Melanosome membrane
CC {ECO:0000250|UniProtKB:O60931}; Multi-pass membrane protein
CC {ECO:0000255}. Note=AP-3 complex is required for localization to the
CC lysosome. {ECO:0000250|UniProtKB:O60931}.
CC -!- DOMAIN: The lysosomal targeting motif, together with te second PQ-loop
CC mediate targeting to the lysosome. {ECO:0000250|UniProtKB:O60931}.
CC -!- DISRUPTION PHENOTYPE: Mice develop ocular damages, bone defects and
CC behavioral anomalies (PubMed:12370309). Defects are caused by cystine
CC accumulation in all organs tested, and formation of cystine crystals
CC (PubMed:12370309). Mice do not develop signs of a proximal tubulopathy
CC or renal failure (PubMed:12370309). Cystine accumulation in the central
CC nervous system causes severe age-related memory deficits: spatial
CC reference and working memory deficits are observed in middle-aged mice
CC (PubMed:17977621). In eyes, cystine crystals induce inflammatory and
CC immune response with aging associated with loss of keratocyte and
CC endothelial cells (PubMed:21897743). Mice show a strong increase in
CC hair pheomelanin content (PubMed:22649030). Decreased mTORC1 signaling
CC pathway in proximal tubular cell lines (PubMed:26449607).
CC {ECO:0000269|PubMed:12370309, ECO:0000269|PubMed:17977621,
CC ECO:0000269|PubMed:21897743, ECO:0000269|PubMed:22649030,
CC ECO:0000269|PubMed:26449607}.
CC -!- SIMILARITY: Belongs to the cystinosin family. {ECO:0000305}.
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DR EMBL; AJ250670; CAC19455.1; -; mRNA.
DR EMBL; AK078511; BAC37316.1; -; mRNA.
DR EMBL; BC005479; AAH05479.1; -; mRNA.
DR CCDS; CCDS25001.1; -.
DR RefSeq; NP_112541.1; NM_031251.4.
DR RefSeq; XP_006534596.1; XM_006534533.3.
DR RefSeq; XP_006534597.1; XM_006534534.3.
DR AlphaFoldDB; P57757; -.
DR STRING; 10090.ENSMUSP00000006103; -.
DR GlyGen; P57757; 6 sites.
DR iPTMnet; P57757; -.
DR PhosphoSitePlus; P57757; -.
DR PaxDb; P57757; -.
DR PRIDE; P57757; -.
DR ProteomicsDB; 284146; -.
DR Antibodypedia; 23081; 199 antibodies from 27 providers.
DR DNASU; 83429; -.
DR Ensembl; ENSMUST00000006103; ENSMUSP00000006103; ENSMUSG00000005949.
DR Ensembl; ENSMUST00000108476; ENSMUSP00000104116; ENSMUSG00000005949.
DR GeneID; 83429; -.
DR KEGG; mmu:83429; -.
DR UCSC; uc007kae.1; mouse.
DR CTD; 1497; -.
DR MGI; MGI:1932872; Ctns.
DR VEuPathDB; HostDB:ENSMUSG00000005949; -.
DR eggNOG; KOG3145; Eukaryota.
DR GeneTree; ENSGT00390000005338; -.
DR HOGENOM; CLU_046327_1_0_1; -.
DR InParanoid; P57757; -.
DR OMA; WIDVIYT; -.
DR OrthoDB; 1138417at2759; -.
DR PhylomeDB; P57757; -.
DR TreeFam; TF313589; -.
DR Reactome; R-MMU-425393; Transport of inorganic cations/anions and amino acids/oligopeptides.
DR Reactome; R-MMU-5223345; Miscellaneous transport and binding events.
DR BioGRID-ORCS; 83429; 2 hits in 73 CRISPR screens.
DR ChiTaRS; Ctns; mouse.
DR PRO; PR:P57757; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; P57757; protein.
DR Bgee; ENSMUSG00000005949; Expressed in lip and 170 other tissues.
DR ExpressionAtlas; P57757; baseline and differential.
DR Genevisible; P57757; MM.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0045111; C:intermediate filament cytoskeleton; ISO:MGI.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0005770; C:late endosome; ISO:MGI.
DR GO; GO:0005765; C:lysosomal membrane; ISS:UniProtKB.
DR GO; GO:0005764; C:lysosome; IDA:MGI.
DR GO; GO:0042470; C:melanosome; ISS:UniProtKB.
DR GO; GO:0033162; C:melanosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0005774; C:vacuolar membrane; IBA:GO_Central.
DR GO; GO:0015184; F:L-cystine transmembrane transporter activity; IDA:MGI.
DR GO; GO:0015295; F:solute:proton symporter activity; ISS:UniProtKB.
DR GO; GO:0007628; P:adult walking behavior; IMP:MGI.
DR GO; GO:0046034; P:ATP metabolic process; ISO:MGI.
DR GO; GO:0007420; P:brain development; ISO:MGI.
DR GO; GO:0050890; P:cognition; ISO:MGI.
DR GO; GO:0006749; P:glutathione metabolic process; ISO:MGI.
DR GO; GO:0007625; P:grooming behavior; IMP:MGI.
DR GO; GO:0015811; P:L-cystine transport; IDA:MGI.
DR GO; GO:0002088; P:lens development in camera-type eye; IMP:MGI.
DR GO; GO:0007616; P:long-term memory; IMP:MGI.
DR GO; GO:0042438; P:melanin biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0010730; P:negative regulation of hydrogen peroxide biosynthetic process; ISO:MGI.
DR GO; GO:1903427; P:negative regulation of reactive oxygen species biosynthetic process; ISO:MGI.
DR GO; GO:0010918; P:positive regulation of mitochondrial membrane potential; ISO:MGI.
DR GO; GO:1904263; P:positive regulation of TORC1 signaling; IMP:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0048021; P:regulation of melanin biosynthetic process; ISS:UniProtKB.
DR GO; GO:0008542; P:visual learning; IMP:MGI.
DR InterPro; IPR005282; LC_transporter.
DR InterPro; IPR006603; PQ-loop_rpt.
DR PANTHER; PTHR13131; PTHR13131; 1.
DR Pfam; PF04193; PQ-loop; 2.
DR SMART; SM00679; CTNS; 2.
DR TIGRFAMs; TIGR00951; 2A43; 1.
PE 1: Evidence at protein level;
KW Glycoprotein; Lysosome; Melanin biosynthesis; Membrane; Protein transport;
KW Reference proteome; Repeat; Signal; Symport; Transmembrane;
KW Transmembrane helix; Transport.
FT SIGNAL 1..22
FT /evidence="ECO:0000250|UniProtKB:O60931"
FT CHAIN 23..367
FT /note="Cystinosin"
FT /id="PRO_0000205515"
FT TOPO_DOM 23..121
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 122..142
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 143..161
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 162..182
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 183..205
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 206..226
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 227..237
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 238..258
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 259..261
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 262..282
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 283..297
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 298..318
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 319..335
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 336..356
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 357..367
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 123..189
FT /note="PQ-loop 1"
FT DOMAIN 263..328
FT /note="PQ-loop 2"
FT MOTIF 362..366
FT /note="Lysosomal targeting motif"
FT /evidence="ECO:0000255"
FT BINDING 305
FT /ligand="H(+)"
FT /ligand_id="ChEBI:CHEBI:15378"
FT /note="protonated residue following cystine-binding"
FT /evidence="ECO:0000250|UniProtKB:O60931"
FT CARBOHYD 36
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 51
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 66
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 84
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 104
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 107
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT MUTAGEN 280
FT /note="K->R: Abolished cystine transport. Abolished
FT interaction with components of the v-ATPase and Ragulator
FT complexes. Does not affect ability to lysosomal
FT localization of LAMP2A."
FT /evidence="ECO:0000269|PubMed:26449607,
FT ECO:0000269|PubMed:28465352"
SQ SEQUENCE 367 AA; 42203 MW; 651DF351189C419E CRC64;
MRRNWLLILT LFLLMFIEKY ESTVSLTAPP TVKLENGSST NVDITLGHPL NSTLVITFEV
TFRSKNLTIV ELPDEVIVPR GEKNASFQVT SQNIGQVTVF LHGNHSNQTC PRIRFLVIHS
RIVSIINQVI GWIYFMAWSV SFYPQVIQNW RRKSVIGLSF DFLALNLTGF VAYSVFNIGL
LWVPYIQEEF LLKYPNGVNP VDSNDAFFSL HAVALTLIVI LQCCLYERGN QRVSWPSIGF
LVLAWLFVLV TMIVAAVGIT TWLQFLFCFS YIKLIITLIK YFPQAYMNFY YKSTKGWSIG
GVLLDFTGGS FSLLQMFLQS YNNDQWTLIF GDPTKFGLGV FTIFFDVVFF IQHFYLYRKK
PGYDQLN
